CA1286684C - Process for the preparation of n-acyl-n-alkyl-2,6- dialkyl-3-chloro-anilines - Google Patents

Abstract

Process for the preparation of N-acyl-N-alkyl-2,6-dialkyl-3-chloro-anilines Abstract of the Disclosure N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of the formula wherein R1 is methyl or ethyl, R2 is alkoxymethyl, chloromethyl or 2-tetrahydrofuryl, R3 is alkoxymethyl, carboxy or alkoxycarbonyl and R4 is hydrogen or methyl and, if R3 is carboxy or alkoxycarbonyl, R4 is also 2-alkoxyethyl and 2-alkoxypropyl, and R3 and R4, together with the carbon atom to which both radicals are attached, may also form a 2-oxotetrahydro-3-furyl radical or a 2-oxo-5-methyltetra-hydro-3-furyl radical, are prepared by reacting a 2,6-dialkylaniline of the formula with a halide of the formula wherein X is chlorine or bromine, to give an N-alkyl-2,6-dialkyl-aniline of the formula then converting said compound by further reaction with an acylating agent of the formula wherein X1 is chlorine, bromine or -O-CO-R2, into an N-acyl-N-alkyl-2,6-dialkylaniline of the formula

Description

12866~

5-16062/~

Process for the preparation of N-acyl-N-alkyl-2,6-dialkyl-3-chloro-anilines The present invention relates to a process for the preparation of N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I
Cl\ /R~ ~4 H-R3 (I) .=.\ C0-R2 wherein R1 is methyl or ethyl, R2 is alkoxymethyl, chloromethyl or 2-tetrahydrofuryl, R3 is alkoxymethyl, carboxy or alkoxycarbonyl and R4 is hydrogen or methyl and, if R3 i9 carboxy or alkoxycarbonyl, R4 is also 2-alkoxyethyl and 2-alkoxypropyl, and R3 and R4, together with the carbon atom to which both radicals are attached, may also form a 2-oxotetrahydro-3-furyl radical or a 2-oxo-5-methyltetra-hydro-3-furyl radical.

Some of the compounds of formula I have fungicidal activity and some of them have herbicidal activity~ Compounds of this type are described for example in US patent specifications 4 564 629 and 3 933 860, British patent specification 1 455 471, published European patent application 0 028 011 and published British patent application 2 006 783.

It is known from published British patent application 2 098 210 to prepare N-acylated N-alkoxycarbonylmethyl-2,6-dialkyl-3-haloanilines and N-(l-alkoxycarbonylethyl)-2,6-dialkyl-3-haloanilines by reacting 12866~4 halogen with corresponding N-alkoxycarbonylmethyl-2,6-dialkyl-anilines and N-(1-alkoxycarbonylethyl)-2,6-dialkylanilines in the presence of at least 2 moles of Lewis acid per mole of N-alkoxy-carbonylalkyl-2,6-dialkylaniline, and subsequently acylating the resultant N-alkoxycarbonylmethyl-2,6-dialkyl-3-haloanilines and N-(l-alkoxycarbonylethyl)-2,6-dialkyl-3-haloanilines. Suitable Lewis acids are aluminium chloride, aluminium bromide, boron trifluoride, tin tetrachloride and titanium tetrachloride. This process i9 disadvantageous in that very large amounts of Lewis acid have to be employed in order to obtain the desired effect. For example, 2 parts by weight of aluminium chloride are necessary per part of N-alkoxy-carbonylalkyl-2,6-dialkylaniline. Since this large amount of aluminium chloride must first be decomposed with water before the reaction mixture is worked up, not only i8 the process costly with respect to the starting materials and auxiliaries required, but it is also complicated to perform.

It is also known to prepare 3-chloro-2,6-dimethylacetanilide in a yield of 80 % of theory by chlorinating 2,6-dimethylacetanilide (q.v. Synthsesis, 1971, p. 467). In accordance with this method, the N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I are obtainable by acetylating a corresponding 2,6-dialkylaniline, chlorinating the 2,6-dialkylacetanilide, hydrolysing the resultant 3-chloro-2,6-dialkylacetanilido to give the 3-chloro-2,6-dialkyl-aniline, alkylating said compound and subsequently effecting acylation according to the following scheme:

-NHz --~~ ~ -NH-COCH3 --~~ ~ NH-COCH3 \Rl \Rl R

\--NH-C~H-R3 ~~~
R

lZt 36~8~

In accordance with this method, the N-acyl-N-alkyl-2,6-dlalkyl-3-chloroanllines of formula I can be prepared in a yield of about 40 ~o of theory, based on the starting 2t6-dialkyldianiline. This method is complicated on account of the large number of reaction steps required and is unsatisfactory with respect to the yields which can be obtained.

It is therefore the object of the present invention to provide a process which makes it possible to prepare the N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I in simple manner and in good yield.

It has been found that this object can be advantageously accom-plished by converting a corresponding 2,6-dialkylaniline by alkyl-ation and subsequent acylation into a corresponding N-acyl-N-alkyl-2,6-dialkylaniline, and then converting said compound by reaction with chlorine into an N-acyl-N-alkyl-2,6-dialkyl-3-chloroaniline of formula I.

In accordance with the present invention~ it is therefore proposed to prepare the N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I by reacting a 2,6-dialkylaniline of formula II

._./
~ ~--NHz (II) \Rl wherein R1 is as defined for formula I, with a halide of formula III

X- ~ -R3 (III) wherein R3 and R4 are as defined for formula I and X is chlorine or bromine, to give an N-alkyl-2,6-dialkylaniline of formula IV
/RI
~ ~--NH-~H-R3 (IV) Rl 12~3~68~

wherein Rl, R3 and R4 are as defined for formula I, then reacting the N-alkyl-2,6-dialkylaniline of formu]a IV wlth an acylating agent of formula V
xl-cO-R2 (V) wherein R2 is as defined for formula I and Xl is chlorine, bromine or -O-CO-Rz, and subsequently converting the resultant N-acyl-N-alkyl-2,6-dialkylaniline of formula VI

H-R3 (VI) .=. CO-R2 I

wherein Rl, R2, R3 and R4 are as defined for formula I, by reaction with chlorine into an N-acyl-N-alkyl-2,6-dialkyl-3-chloroaniline of formula I.

Suitable 2,6-dialkylanilines of formula II are 2,6-dimethylaniline and 2,6-diethylaniline. 2,6-Dimethylaniline is particularly suitable.

Suitable halides of formula III are 2-alkoxyethyl chloride, 2-alkoxyethyl bromide, 2-alkoxypropyl chloride, 2-alkoxypropyl bromide, 2-chloroacetic acid, 2-bromoacetic acid, 2-chloroproplonlc acid, 2-bromopropionic acid, 2-chloroacetic acid alkyl esters, 2-bromoacetic acld alkyl esters, 2-chloropropionic acid alkyl esters, 2-bromopropionic acld alkyl esters, 2-chloro-4-alkoxybutyric acid, 2-bromo-4-alkoxybutyric acid, 2-chloro-4-alkoxyvaleric acid, 2-bromo-4-alkoxyvaleric acid, 2-bromo-4-alkoxybutyric acid alkyl esters, 2-bromo-4-alkoxybutyric acid alkyl esters, 2-chloro-4-alkoxyvaleric acid alkyl esters, 2-bromo-4-alkoxyvaleric acid alkyl esters, ~-chloro-~-butyrolactone, ~-bromo-r-butyrolactone, ~-chloro-r-valerolactone and ~-bromo-~-valerolactone. ~he alkoxy and alkyl ester groups present in said halides of formula III contain alkyl radicals each of 1 to 4 carbon atoms. Specifically, said alkyl radicals may be methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.

lZ~661Y4 When uslng halides of formula III wherein X i8 chlorine, the reactlon of a 2,6-dlalkylanlllne of formula II with the halide of formula III is advantageously carried out ln the presence of an alkall metal lodide, in partlcular potassium lodide, as catalyst.

Preferred halides of formula III are 2-methoxyethyl chlorlde, 2-ethoxyethyl chlorlde, 2-methoxy-1-methylethyl chloride, methyl 2-chloroacetate, ethyl 2-chloroacetate, methyl 2-bromopropionate, ethyl 2-bromoproplonate and u-chloro-y-butyrolactone. A partlcularly preferred hallde of formula III is ~-bromo-y-butyrolactone.

Suitable acylating agents of formula V are chlorides and bromldes of chloroacetic acld, alkoxyacetic acid and tetrahydrofuran-2-car-boxylic acid as well as the anhydrides of these acids. Alkoxyacetic acids shall be understood as meaning in particular those containing a C~-C"alkoxy radical such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and isobutoxy. Preferred acylating agents are methoxyacetyl chloride, chloroacetyl chloride and tetrahydrofuran-2-carboxyllc acld chloride, with methoxyacetyl chloride being particularly preferred.

The reaction of a 2,6-dialkylaniline of formula II with a halide of formula III is advantageously carried out ln an inert solvent in the presence of an acid acceptor. Suitable lnert solvents are aromatic hydrocarbons and hydrogenated hydrocarbons such as benzene, toluene, xylene, chlorobenzene and o-dichlorobenzene, as well as N,N-disub-stituted carboxamides such as N,N-dimethylformamide and N,N-dimethy-acetamide, and also excess 2,6-dialkylaniline of formula II. Pre-ferred solvents are toluene and xylene. Suitable acid acceptors are inorganic and organic bases such as alkali metal hydroxides, carbonates and bicarbonates, alkaline earth metal hydroxides, carbonates and bicarbonates, triethylamine, pyridine or excess 2,6-dialkylaniline of formula II. A preferred base is sodium carbonate. The reaction temperatures are as a rule in the range from 80C to the reflux temperature of the reaction medium. It is 12~ 4 advantageous to carry out the alkylation at the reflux temperature of the reaction medium. The reaction of a 2,6-dialkylaniline of formula II with a halide of formula III is therefore preferably carried out in toluene or xylene as solvent, in the presence of sodium carbonate as acid acceptor and at the reflux temperature of the reaction medium.

The reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V is advantageously carried out in an inert solvent in the absence or presence of an acid acceptor.
Suitable inert solvents are in particular water-immiscible solvents such as aliphatic and aromatic hydrocarbons and halogenated hydro-carbons. Examples of suitable solvents are hexane, benzene, toluene, xylene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride and ethylene chloride. Preferred solvents are toluene and xylene.

Suitable acid acceptors in the presence of which the reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V can be carried out are inorganic and organic bases such as alkali metal hydroxides, carbonates and bicarbonates, alkaline earth metal hydroxides, carbonates and bicarbonates, triethylamine and pyridine. The reaction of an N-alkyl-2,6-dialkylaniline of fo-rmula IV with an acylating agent of formula V is preferably carried out in the absence of a base, in toluene or xylene and under reduced pressure. Suitable pressures under which the reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V can be carried out are in the range from 50 to 150 mbar, preferably from 60 to 100 mbar.

The chlorination of an N-acyl-N-alkyl-2,6-dikalkylaniline of formula VI is also advantageously carried out in an inert solvent.
Suitable solvents are in particular lower aliphatic carboxylic acids such as formic acid and acetic acid. Further suitable solvents are chlorinated aromatic and aliphatic hydrocarbons such as chloro-benzene, methylene chloride, chloroform, carbon tetrachloride and ~2~6684 ethylene chloride. The carboxylic acids employed as solvents may contain up to 60 % by weight of water. A preferred solvent in whlch the chlorination of an N-acyl-N-alkyl-2,6-dialkylanillne of for-mula VI can be carried out is formic acid ~ith a water content of up to 40 % by weight.

The chlorination is advantageously carried out in the temperature range from 20 to 40C. The chlorination can also be carried out either at more elevated or at lower temperatures. However, it must be borne in mind that at temperatures above 40C increasingly dichlorinated products are formed, whereas at temperatures below 20C there is a danger that the reaction will no longer begin immediately on commencement of the introduction of chlorine, but will only start when a relatively high concentration of chlorine has built up. This delayed-start reaction is often very vigorous and it ls difficult to control the temperature of the reaction mixture. In this case the formation of dichlorinated products must also be expected.

It i8 also advantageous to carry out the chlorination in the presence of Lewis acids such as aluminlum chloride, iron(III) chloride, boron trifluoride and titanium tetrachloride. Iron(III) chloride is a preferred Lewis acid. The Lewis acids are employed in an amount of l to 5 % by weight, preferably l.5 to 2.5 % by weight, based on the N-acyl-N-alkyl-2,6-dialkylaniline of formula VI to be chlorinated. The Lewls acids do not as such have a substantial influence on the chlorination, however they greatly increase the solubility in aqeuDus formic acid or aqueous acetic acid of the N-acyl-N-alkyl-2,6-dialkylanilines of formula VI to bè chlorinated.
Therefore, in order to obtain a higher volume yield, it is advisable to add Lewis acids in particular when emplyoying formic acid or acetic acid as solvent. The chlorination of an N-acyl-N-alkyl-2,6-dialkylaniline of formula VI is thus preferably carried out in the temperature range from 20 to 40C, in formic acid with a water content of up to 40 % by weight and in the presence of 1.5 to 2.5 %
by weight of iron(III) chloride, based on the N-acyl-N-alkyl-2,6-dialkylaniline of formula VI employed.

The chlorination is usually carried out under normal pressure. When using formic acid or acetic acid as solvent, the reaction may be carried out under slightly excess pressure since no gas escapes from the reaction mixture when these solvents are in use.

The process of the present invention makes it possible to prepare the N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I from 2,6-dialkylanilines of formula II in simple manner and in a sub-stantially better yield than by the known processes. Compared with the process described in published British patent applica-tion 2 089 210, which process is 'oased on the chlorination of N-alkyl-2,6-dialkylanilines in the presence of at least 2 moles of a Lewis acid, the use of large amounts of Lewis acid and the con-comitant difficulties in working up can be avoided. Compared with the process mentioned at the outset which is based on the chlorina-tion of N-acetyl-2,6-dialkylanilines, two reaction steps can be dispensed with, i.e. the introduction of the acetyl group before chlorination and the removal thereof after chlorination. The N-alkylation of 2,6-dialkylanilines affords better yields than the corresponding N-alkylation of 2,6-dialkyl-3-chloroanilines. More-over, surprisingly, the chlorination of N-acyl-N-alkyl-2,6-di-alkylanilines of formula VI affords better yields than the known chlorination of 2,6-dialkylacetanilides. The concept of the present invention makes it possible for the first time to utilise these sdvantages. It i9 an essential feature of this concept that the introduction of the chlorine atom into the 3-positon of the phenyl radical i8 carried out in the final step.

The process of the present invention is illustrated in more detail by the following Example.

lZ8661~34 g Example 1: Preparatlon of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-3-chloro-2,6-dlmethylaniline a~ 64 g (O 6 mole) of anhydrous sodium carbonate solution are suspended in a solution of 121 g (1.0 mole) of 2,6-dimethylaniline in 500 ml of xylene. Over 2 hours, 206 g (1.25 moles) of ~-bromo-y-butyrolactone (3-bromo-2-oxotetrahydrofuran) are added to this suspension at reflux temperature (about 140C). When the addition of the ~-bromo-~-butyrolactone is complete, the reaction mixture is stirred for 4 hours at room temperature. The water of reaction is removed during the addition of the ~-bromo-~-butyrolactone and during the subsequent stirring. The reaction mixture is then cooled to 50C, washed first wlth 200 ml of water and then with 200 ml of 5 % hydrochloric acid and subsequently dried by distilling off 50-60 ml of solvent. According to gas chromatographic analysis, the reaction mixture contains 174 g (~5 % of theory) of N-(2-oxotetra-hydro-3-furyl)-2,6-dimethylaniline, part of which precipitates when the reaction mixture cools. The resultant suspension can be further processed direct in the next step. However, the product may also be recovered by distilling off the solvent and crystallising the residue from isopropanol. The melting point is 82-84C.

b) Over 2 hours, 113 g (1.04 moles) of methoxyacetyl chloride are added at 60-70C and under a pressure of 70-80 mbar to a suspension of 205 g (1.0 mole) of N-(2-oxotetrahydro-3-furyl)-2,6-dimethyl-aniline in 500 ml of xylene. Towards the end of the addition of methoxyacetyl chloride the reaction mixture begins to boil, with hydrogen chloride gas evolving. When the addition of methoxyacetyl chloride is complete, the reaction mixture is stirred for 3 hours under weak reflux at 60-65C and under a pressure of 70-80 mbar, and the hydrogen chloride evolving during the reaction is removed.
Subsequently, half of the xylene is distilled off, the reaction mixture is cooled to 20C, the precipitated product is filtered off, washed with xylene and dried, affording 263 g (95 % of theory) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline with a melting point of 118-120C.

~2~36684 c~ Over 2 hours, 74.6 g (1.05 moles) of chlorine are introduced at 25-30C into a solution of 277 g (1.0 mole) of N-methoxyacetyl-N-(2-oxotetrahy~ro-3-furyl)-2,6-dimethylaniline and 5 g of iron(III) chloride in 300 ml of 85 % formic acid. The reaction is exothermic and virtually no gas evolves. ~hen the addition of chlorine is complete, the reaction mixture is stirred for 30 minutes at 25~C, the formic acid is then distilled off in vacuo, the residue is taken up in 500 ml of toluene and the toluenic solution is washed with 100 ml of water. The oily residue obtained after the toluene has been distilled off is crystallised from a mixture of isopropanol and hexane, affording 287 g (92 % of theory) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-3-chloro-2,6-dimethylaniline with a melting point of 80-82C.

Claims (27)

1. A process for the preparation of an N-acyl-N-alkyl-2,6-dialkyl-3-chloroaniline of formula I
(I) wherein R1 is methyl or ethyl, R2 is alkoxymethyl, chloromethyl or

2-tetrahydrofuryl, R3 is alkoxymethyl, carboxy or alkoxycarbonyl and R4 is hydrogen or methyl and, if R3 is carboxy or alkoxycarbonyl, R4 is also 2-alkoxyethyl and 2-alkoxypropyl, and R3 and R4, together with the carbon atom to which both radicals are attached, may also form a 2-oxotetrahydro-3-furyl radical or a 2-oxo-5-methyltetra-hydro-3-furyl radical, which process comprises reacting a 2,6-di-alkylaniline of formula II

(II) wherein R1 is as defined for formula I, with a halide of formula III

(III) wherein R3 and R4 are as defined for formula I and X is chlorine or bromine, to give an N-alkyl-2,6-dialkylaniline of formula IV

(IV) wherein R1, R3 and R4 are as defined for formula I, then reacting the N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V
X1-CO-R2 (V) wherein R2 is as defined for formula I and X1 is chlorine, bromine or -O-CO-R2, and subsequently converting the resultant N-acyl-N-alkyl-2,6-dialkylaniline of formula VI

(VI) wherein R1, R2, R3 and R4 are as defined for formula I, by reaction with chlorine into an N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilire of formula I.

2. A process according to claim 1, wherein the 2,6-dialkylaniline of formula II is 2,6-dimethylaniline or 2,6-diethylaniline.

3. A process according to claim 2, wherein the 2,6-dialkylaniline of formula II is 2,6-dimethylaniline.

4. A process according to claim 1, wherein the halide of for-mula III is 2-methoxyethyl chloride, 2-ethoxyethyl chloride, 2-methoxy-1-methylethyl chloride, methyl 2-chloroacetate, ethyl 2-chloroacetate, methyl 2-bromopropionate, ethyl 2-bromopropionate or .alpha.-bromo-.gamma.-butyrolactone.

5. A process according to claim 4, wherein the halide of formula III
is .alpha.-bromo-.gamma.-butyrolactone.

6. A process according to claim 1, wherein the acylating agent of formula V is methoxyacotyl chloride, chloroacetyl chloride or tetrahydrofuran-2-carboxylic acid chloride.

7. A process according to claim 6, whewrein the acylating agent of formula V is methoxyacetyl chloride.

8. A process according to claim 1, wherein the reaction of a 2,6-dialkylaniline of formula II with a halide of formula III is carried out in an inert solvent and in the presence of an acid acceptor.

9. A process according to claim 8, wherein the inert solvent is benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, N,N-di-methylformamide or N,N-dimethylacetamide.

10. A process according to claim 8, wherein the inert solvent is toluene or xylene.

11. A process according to claim 8, wherein the acid acceptor is an alkali metal hydroxide, carbonate or bicarbonate, an alkaline earth metal hydroxide, carbonate or bicarbonate, triethylamine or pyridine.

12. A process according to claim 8, wherein the acid acceptor is sodium carbonate.

13. A process according to claim 1, wherein the reaction of a 2,6-dialkylaniline of formula II with a halide of formula III is carried out at a temperature in the range from 80°C to the reflux temperature of the reaction medium.

14. A process according to claim 13, wherein the reaction of a 2,6-dialkylaniline of formula II with a halide of formula III is carried out at the reflux temperature of the reaction medium.

15. A process according to claim 1, wherein the reaction of a 2,6-dialkylaniline of formula II with a halide of formula III is carried out in toluene or xylene as solvent, in the presence of sodium carbonate as acid acceptor and at the reflux temperature of the reaction medium.

16. A process according to claim 1, wherein the reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V is carried out in an inert solvent.

17. A process according to claim 16, wherein the reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V is carried out in hexane, benzene, toluene, xylene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride or ethylene chloride as solvent.

18. A process according to claim 16, wherein the reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V is carried out in toluene or xylene as solvent.

19. A process according to claim 1, wherein the reaction of an N-alkyl-2,6-dialkylaniline of formula IV with an acylating agent of formula V is carried out in the absence of a base, in toluene or xylene as solvent and under reduced pressure.

20. A process according to claim 1, wherein the chlorination of an N-acyl-N-alkyl-2,6-dialkylaniline of formula VI is carried out in an inert solvent.

21. A process according to claim 20, wherein the inert solvent is formic acid, acetic acid, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride or ethylene chloride.

22. A process according to claim 20, wherein the inert solvent is formic acid or acetic acid with a water content of up to 40 % by weight.

23. A process according to claim 1, wherein the chlorination of an N-acyl-N-alkyl-2,6-dialkylaniline of formula VI is carried out in the temperature range from 20° to 40°C.

24. A process according to claim 1, wherein the chlorination of an N-acyl-N-alkyl-2,6-dialkylaniline of formula VI is carried out in the presence of 1 to 5 % by weight of a Lewis acid.

25. A process according to claim 24, wherein the Lewis acid is aluminium chloride, iron(III) chloride, boron trifluoride or titanium tetrachloride.

26. A process according to claim 24, wherein the Lewis acid is iron(III) chloride.

27. A process according to claim 1, wherein the chlorination of an N-acyl-N-alkyl-2,6-dialkylaniline of formula VI is carried out in the temperature range from 20° to 40°C, in formic acid with a water content of up to 40 % by weight and in the presence of 1.5 to 2.5 %
by weight of iron(III) chloride, based on the N-acyl-N-alkyl-2,6-di-alkylaniline of formula VI employed.

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