Process for the preparation of N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines

N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of the formula ##STR1## wherein R.sub.1 is methyl or ethyl, R.sub.2 is alkoxymethyl, chloromethyl or 2-tetrahydrofuryl, R.sub.3 is alkoxymethyl, carboxy or alkoxycarbonyl and R.sub.4 is hydrogen or methyl and, if R.sub.3 is carboxy or alkoxycarbonyl, R.sub.4 is also 2-alkoxyethyl and 2-alkoxypropyl, and R.sub.3 and R.sub.4, 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-methyltetrahydro-3-furyl radical, are prepared by reacting a 2,6-dialkylaniline of the formula ##STR2## with a halide of the formula ##STR3## wherein X is chlorine or bromine, to give an N-alkyl-2,6-dialkylaniline of the formula ##STR4## then converting said compound by further reaction with an acylating agent of the formula EQU X.sub.1 --CO--R.sub.2 wherein X.sub.1 is chlorine, bromine or -O-CO-R.sub.2, into an N-acyl-N-alkyl-2,6-dialkylaniline of the formula ##STR5## and subsequently converting said compound by reaction with chlorine into an N-acyl-N-alkyl-2,6-dialkyl-3-chloroaniline of the above formula.

The present invention relates to a process for the preparation of 
N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I 
##STR6## 
wherein R.sub.1 is methyl or ethyl, R.sub.2 is alkoxymethyl, chloromethyl 
or 2-tetrahydrofuryl, R.sub.3 is alkoxymethyl, carboxy or alkoxycarbonyl 
and R.sub.4 is hydrogen or methyl and, if R.sub.3 is carboxy or 
alkoxycarbonyl, R.sub.4 is also 2-alkoxyethyl and 2-alkoxypropyl, and 
R.sub.3 and R.sub.4, 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-methyltetrahydro-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 U.S. Pat. Nos. 4,564,629 and 3,933,860, British patent 
specification No. 1 455 471, published European patent application No. 0 
028 011 and published British patent application No. 2 006 783. 
It is known from published British patent application No. 2 098 210 to 
prepare N-acylated N-alkoxycarbonylmethyl-2,6-dialkyl-3-haloanilines and 
N-(1-alkoxycarbonylethyl)-2,6-dialkyl-3-haloanilines by reacting halogen 
with corresponding N-alkoxycarbonylmethyl-2,6-dialkylanilines and 
N-(1-alkoxycarbonylethyl)-2,6-dialkylanilines in the presence of at least 
2 moles of Lewis acid per mole of 
N-alkoxycarbonylalkyl-2,6-dialkylaniline, and subsequently acylating the 
resultant N-alkoxycarbonylmethyl-2,6-dialkyl-3-haloanilines and 
N-(1-alkoxycarbonylethyl)-2,6-dialkyl-3-haloanilines. Suitable Lewis acids 
are aluminium chloride, aluminium bromide, boron trifluoride, tin 
tetrachloride and titanium tetrachloride. This process is 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-alkoxycarbonylalkyl-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 is 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-dialkylacetanilide to give the 3-chloro-2,6-dialkylaniline, 
alkylating said compound and subsequently effecting acylation according to 
the following scheme: 
##STR7## 
In accordance with this method, the 
N-acyl-N-alkyl-2,6-dialkyl-3-chloroanilines of formula I can be prepared 
in a yield of about 40% of theory, based on the starting 
2,6-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 accomplished by 
converting a corresponding 2,6-dialkylaniline by alkylation 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 
##STR8## 
wherein R.sub.1 is as defined for formula I, with a halide of formula III 
##STR9## 
wherein R.sub.3 and R.sub.4 are as defined for formula I and X is chlorine 
or bromine, to give an N-alkyl-2,6-dialkylaniline of formula IV 
##STR10## 
wherein R.sub.1, R.sub.3 and R.sub.4 are as defined for formula I, then 
reacting the N-alkyl-2,6-dialkylaniline of formula IV with an acylating 
agent of formula V 
EQU X.sub.1 --CO--R.sub.2 (V) 
wherein R.sub.2 is as defined for formula I and X.sub.1 is chlorine, 
bromine or --O--CO--R.sub.2, and subsequently converting the resultant 
N-acyl-N-alkyl-2,6-dialkylaniline of formula VI 
##STR11## 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined for formula 
I, by reaction witb chlorine into an 
N-acyl-N-alkyl-2,6-dialkyl-3-chloroaniline of formula 1. 
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-chloropropionic acid, 2-bromopropionic acid, 
2-chloroacetic acid alkyl esters, 2-bromoacetic acid alkyl esters, 
2-chloropropionic acid alkyl esters, 2-bromopropionic acid 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, 
.alpha.-chloro-.gamma.-butyrolactone, .alpha.-bromo-.gamma.-butyrolactone, 
.alpha.-chloro.gamma.-valerolactone and 
.alpha.-bromo-.gamma.-valerolactone. The 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. 
When using halides of formula III wherein X is chlorine, the reaction of a 
2,6-dialkylaniline of formula II with the halide of formula III is 
advantageously carried out in the presence of an alkali metal iodide, in 
particular potassium iodide, as catalyst. 
Preferred halides of formula III are 2-methoxyethyl chloride, 2-ethoxyethyl 
chloride, 2-methoxy1-methylethyl chloride, methyl 2-chloroacetate, ethyl 
2chloroacetate methyl 2-bromopropionate, ethyl 2-bromopropionate and 
.alpha.-chloro-.gamma.-butyrolactone. A particularly preferred halide of 
formula III is .alpha.-bromo-.gamma.-butyrolactone. 
Suitable acylating agents of formula V are chlorides and bromides of 
chloroacetic acid, alkoxyacetic acid and tetrahydrofuran-2-carboxylic acid 
as well as the anhydrides of these acids. Alkoxyacetic acids shall be 
understood as meaning in particular those containing a C.sub.1 -C.sub.4 
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-carboxylic acid 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 in an inert solvent in the presence of 
an acid acceptor. Suitable inert solvents are aromatic hydrocarbons and 
hydrogenated hydrocarbons such as benzene, toluene, xylene, chlorobenzene 
and o-dichlorobenzene, as well as N,N-disubstituted carboxamides such as 
N,N-dimethylformamide and N'N-dimethyacetamide, and also excess 
2,6-dialkylaniline of formula II. Preferred 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 80.degree. C. to 
the reflux temperature of the reaction medium. It is 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 hydrocarbons. 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 formula 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 chlorobenzene, methylene chloride, 
chloroform, carbon tetrachloride and ethylene chloride. The carboxylic 
acids employed as solvents may contain up to 60% by weight of water. A 
preferred solvent in which the chlorination of an 
N-acyl-N-alkyl-2,6-dialkylaniline of formula VI can be carried out is 
formic acid with a water content of up to 40% by weight. 
The chlorination is advantageously carried out in the temperature range 
from 20.degree. to 40.degree. C. 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 40.degree. C. increasingly 
dichlorinated products are formed, whereas at temperatures below 
20.degree. C. 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 is difficult to 
control the temperature of the reaction mixture. In this case the 
formation of dichlorinated products must also be expected. 
It is also advantageous to carry out the chlorination in the presence of 
Lewis acids such as aluminium 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 1 to 5% by 
weight, preferably 1.5 to 2.5% by weight, based on the 
N-acyl-N-alkyl-2,6-dialkylaniline of formula VI to be chlorinated. The 
Lewis acids do not as such have a substantial influence on the 
chlorination, however they greatly increase the solubility in aqeuous 
formic acid or aqueous acetic acid of the 
N-acyl-N-alkyl-2,6-dialkylanilines of formula VI to be 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-2,6dialkylaniline of 
formula VI is thus preferably carried out in the temperature range from 
20.degree. to 40.degree. 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-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 substantially 
better yield than by the known processes. Compared with the process 
described in published British patent application No. 2 089 210, which 
process is based on the chlorination of N-alkyl-2,6-dialkylaniline in the 
presence of at least 2 moles of a Lewis acid, the use of large amounts of 
Lewis acid and the concomitant difficulties in working up can be avoided. 
Compared with the process mentioned at the outset which is based on the 
chlorination 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. Moreover, surprisingly, the 
chlorinarion of N-acyl-N-alkyl-2,6-dialkylanilines 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 time 
to utilize these advantages. It is an essential feature of this concept 
that the introduction of the chlorine atom into the 3-position of the 
phenyl radical is carried out in the final step.

The process of the present invention is illustrated in more detail by the 
following Example. 
EXAMPLE 1 
Preparation of 
N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-3-chloro-2,6-dimethylaniline 
(a) 64 g (0.6 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 .alpha.-bromo-.gamma.-butyrolactone 
(3-bromo-2-oxotetrahydrofuran) are added to this suspension at reflux 
temperature (about 140.degree. C.). When the addition of the 
.alpha.-bromo-.gamma.-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 .alpha.-bromo-.gamma.-butyrolactone and during 
the subsequent stirring. The reaction mixture is then cooled to 50.degree. 
C., washed first with 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 (85% of theory) of 
N-(2-oxotetrahydro-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.degree.-84.degree. C. 
(b) Over 2 hours, 113 g (1.04 moles) of methoxyacetyl chloride are added at 
60.degree.-70.degree. C. and under a pressure of 70.degree.-80 mbar to a 
suspension of 205 g (1.0 mole) of 
N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline 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.degree.-65.degree. C. 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 20.degree. C., 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.degree.-120.degree. C. 
(c) Over 2 hours, 74.6 g (1.05 moles) of chlorine are introduced at 
25.degree.-30.degree. C. into a solution of 277 g (1.0 mole) of 
N-methoxyacetyl-N-(2-oxotetrahydro-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. When the addition of chlorine is 
complete, the reaction mixture is stirred for 30 minutes at 25.degree. 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.degree.-82.degree. C.