Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
-- 2 --
The invention relates to an improved process
for the preparation of diphenyl ethers of general
formula
Xl NHR2
( l)n ~ X~ ~I2 (I)
wherein
n is an integer from 1 to 3,
Rl represents hydrogen, halogen, alkyl or alkoxy
with 1 to 8 carbon atoms, trifluoromethyl, acetyl
or cyano,
R2 represents hydrogen; alkyl, alkenyl or alkynyl
with up to 16 carbon atoms; an alkyl group with 2
to 6 carbon atoms substituted by hydroxyl Cl 4 alkoxy,
phenoxy, halophenoxy, Cl 4 alkylphenoxy, Cl 4 alkoxyphenoxy,
nitrophenoxy, cyanophenoxy, amino or Cl 4 alkylthio;
optionally halosubstituted benzyl, NR3R4, CHR3-COOR~
or CHR3-CONR4R5, wherein R3, R4 and R5, which may
be the same or different, represent hydrogen or Cl 8
alkyl groups, and
Xl and X2, which may be the ~-same or di~ferant/
represent hydeogen or halogen arld Xl a~ rep~e(3~nt~s
methy 1 .
n will only assume the values 2 and 3 if R
represents halogen or alkyl. The term "halogen"
refers to fluorine, chlorine, bromine and iodine.
The preferred halogens are fluorine, chlorine and
bromine, particularly fluorine and chlorine. When
Rl, R2, R3, R4 and R5 represent or contain hydrocarbon
gro~ps, these may possibly also be branched. However,
these groups preferably contain 1 to 2 carbon atoms.
.,j ,.
` ` ~2~;~7~:3
Within the scope of the definitions given herein-
before, Rl preferably represents hydrogen, fluorine,
chlorine, bromine or methyl, R2 represents hydrogen,
Cl 4 alkyl, allyl, 2-hydroxyethyl, 4-fluoro- or 4-
chlorobenzyl or dimethylamino. R3 is preferably
hydrogen or methyl whilst R4 is Cl 4 alkyl. The
preferred definitions of Xl/X2 are chlorine/hydrogen,
methyl/hydrogen, chlorine/bromine and bromine/chlorine.
If n represents 2 or 3, there may be different groups
Rl present at the same time. Some of the compounds
of general formula I are known (DE-OS P 29 38 595).
They are distinguished by their excellent herbicidal
action.
According to DE-OS 29 38 595 the compounds
of general formula I can be obtained by reacting
a nitrodiphenoxybenzene of general formula
(Rl)n~
wherein n, Rl, Xl and X2 are a~ hereinbefore defined,
with an amine of formula
H2NR2 (III)
wherein R2 is as hereinbefore defined, at elevated
temperature. The compounds of formula II are prepared
by reacting a compound of general formula
~ Ei4763
Xl Cl
Ll
Cl ~ NO2 ~IV)
X2
wherein Xl and X2 are as hereinbefore defined, for
example 2,3,4-trichlorobenzene, 2,4-dichloro-3-methyl-
nitrobenzene and 2,3,4,5-tetrachloronitrobenzene,
with a corresponding phenoxide of general formula
(Rl)2
~ OKat (V)
(wherein Kat is one equivalent of a cation). Preferably,
the alkali metal phenoxides are used, particularly
the sodium phenoxide, or the phenol and, for example,
an alkali metal carbonate. In the case of simple
phenols, particularly unsubstituted phenol, the corres-
ponding phenol may servc ~s a rea~tion mec~lum. Ilowever,
it is par~icul~rly pre~crred to use dlmeth~lsulphoxide
as solvent
The two chlorine atoms in the 2- and 4-positions,
which can be exchanged for phenoxy groups, show a
clearly graduated reactivity.
The known process is less suitable for use
on an industrial scale. In the production of the
starting substances of formula II, strongly coloured
by--products are formed which make it difficult or
~2~497~i3
-- 5 --
impossible to carry out further processing directly.
further problem is presented by phenolic by-products,
e g. cleavage products of the type
Xl OH
(Rl)n X~
An extensive purifying operation is needed to eliminate
the by-products.
The reaction of the compounds of formula II
to yield the end products of formula I according
to the prior art requires, in some cases, an autoclave
reaction in solvents such as toluene, dioxan or chlorinated
hydrocarbons. Substantial reaction times (about
12 to 20 hours) are generally required.
It has now been found that the compounds of
formula I can be obtained with greater purity, in
a shorter time and with less elaborate apparatus,
if a nitrobenzene of formula IV is heterogeneously
reacted, in the presence of a phase transfer catalyst,
with a phen~l of formula
(Rl)n Ol~ ~VX)
wherein Rl and n are as hereinbefore defined, with
the addition of an aqueous alkaline or alkaline earth
metal base, at elevated temperature, to ~orm the
corresponding 2,4-diphenoxy compound of formula II,
which i5 then reacted, in a hiyh-boiling alcohol
~L26~7~i3
-- 6 --
containing ether groups, with an amine o~ formula
III to form the corresponding compound of formula
I.
If desired, the first reaction step, which
produces the diphenoxy compounds of formula II, may
also be carried out with the addition of inert, water-
immiscible solvents. The critical advantage of the
reaction according to the invention consists in the
use of a conventional phase transfer catalyst. Thanks
to the addition of such a catalyst, a very pure product
of formula II is obtained in an excellent yield at
temperatures of between 60 and 150C, preferably
between 80 and 120C, more particularly between 90
and 110C. The phase transfer catalyst can be recovered
almost totally. The reaction components of formulae
IV and VI are used in a molar ratio of from 1:1.8
to 1:2.5. Preferably, the phenol is used in a slight
excess (molar ratio 1:2.1 to 1:2.4) and a quantity
of a~ueous base, preferably strong sodium or potassium
hydroxide solution, corresponding to the quantity
of phenol is used. The quantity of phase transfer
catalyst may vary within wide limits. It has proved
advantageous to use about 0.005 to 0.12, preferably
from 0.01 to 0.06 mol of catalyst per mol of phenol.
Suitable phase transfer catalysts include, for example,
triethylbenzylammonium chloride or bromide; tetrabutyl-
ammonium chloride, bromide, hydrogen sulphate, hydroxide;
methyl trioctylammonium chloride; tetra~u~ylphos~honium
bromide. Nllmerous other ~iuitahle ~ha~.se t.~nsE@r
catalysts arè mentioned in the monograph by E.V.
Dehmlow and S.S. Dehmlow, "Phase Transfer Catalysis",
Verlag Chemie, Weinheim (1980), particularly page
38 and pages 39-43.
The second reaction step, the reaction of the
diphenoxy compounds of formula Il to yield the end
products of formula I, is, surprisingly, particularly
successful if ether alcohols are ~sed as the reaction
medium. Suitable compounds of this kind include,
~264763
-- 7 --
in particular, aliphatic or cycloaliphatic compounds,
e.g. diethylene glycol, triethylene glycol, dipropylene
glycol, diethylene glycol monomethyl ether, monoethy~
ether, monopropyl ether, monobutyl ether, monobenzyl
ether, lower monoalkyl ethers of triethylene glycol
or of dipropylene glycol and partial ethers of other
polyhydric alcohols. The reaction temperature is
between about 20 and 180C, preferably between about
40 and 170C; it depends largely on the amine of
formula III used. Whereas methylamine, for example,
can be reacted at ambient temperature, a higher temperature
is required when ammonia is used so that the reaction
can be completed with a few hours. A slight increase
in the ammonia pressure to 3 to 4 bar can be used
to per~orm the reaction at temperatures of about
120 to 130C without taking any longer.
The end products are obtained in very pure
form and in very good yields.
In the Examples which follow, the process is
described more fully, without being restricted to
the embodiments described.
~ 6;~
-- 8
Preparation of diphenoxy__ompounds of formula II
Example (a)
2-Chloro-4-nitro-1,3-diphenoxybenzene
216.2 g (2.3 mol) of phenol, 226.5 g (1 mol)
of 95.5% 2,3,4-trichloronitrobenzene and 10.0 9 of
tetrabutylammonium hydrogen sulphate are heated to
100C in a flask with a stirrer. Within 10 minutes,
187.5 9 of 49% sodium hydroxide solution are added
dropwise, with vigorous stirring. The reaction mixture
is then kept at about 110C for 4 hours. After it
has cooled to about 90C, 1 litre of toluene is added
and then water is added. The aqueous phase is separated
off. The toluene phase is extracted twice with 100 ml
of 2N hydrochloric acid. The toluene layer is separated
off and concentrated by evaporation ln vacuo. According
to gas chromatography, 94.1% of the residue consists
of the title compound. From the crude product, 97.4%
of theory of pure end product is obtained, m.p. 106-
107C.
The catalyst can be recovered from the hydrochloric
acid phase n a yield of more than 90% and sufficiently
pure to be usecl again in the form of the hydrochloride.
Example (b)
3-Methyl-2,4-diphenoxy-nitrobenzene
20.6 y (0.l mol) of 2,4-dichloro-3-methyl-nitro
benzene, 21.6 g (a . ~25 mol) of phenol and 9.3 c~ o(
95% tetrabutylpllosE7honium chlc7rld~ ~0.03 mol) are
placed in a stirring app~ratus and heated to 110C.
27 g (0.3 mol) of 50~ sodium hydroxide solution are
added dropwise to the mixture, with stirring, and
the eesulting mixture is stirred for 2 to 3 hours
at reflux temperature. After cooliny, 100 ml of
toluene and 50 ml of water are added. The mixture
is stirred thoroughly and then the phases are separated.
The toluene solution is extracted with 2N hydrochloric
acid and then with 2N sodium hydroxide solution,
4~7~;3
g
then dried and concentrated by evaporation. A brown
oil is obtained (yield 31.7 g = 99~ of theory) which
crystallises when stirred with a little isopropanol.
The yellowish solid is suction filtered and dried,
m.p. 55-57C.
Some of the tetrabutylphosphonium chloride
is recovered from the acidic washing liquid.
~26~763
-- 10 --
The following compounds may be Qbtained accoedingly.
R" ~ Ll ~ ~/` R
R " ' -r
''2
Example R ~ R." R" ' ;~ 2 Mp
3 H H H Cl Cl 152C
4 4-~ H H Cl H
4-CF3 H H Cl El
6 2-C1 4-Cl El Cl l-l
7 2-C1 4-C1 5-Cl Cl H
8 2-C1 4-Br 5-Cl Cl ri
9 2-CH3 4-Cl H Cl El
2-C1 4-SCEi3 5-Cl Cl H
11 2-CH3 4-CH3 H Cl E~
12 2-CI`I H H Cl H
13 4-F ll 11 Cl-l,, ll
14 4-CF~ El E~ Ct ~
2-F 4-CH~ El CH-~ H
16 2-CH~ 4-CH3 H Cl-l
17 ~ Cl 1~ ~I Cl~
18 2-C1 5-Cl E~. Ei3 I-i
19 4-oCH3 El ~I CH H
3-CF3 H u CH3 ~
~2~i4t76~
Exar~lple R ~ R" R!' r Xl X Mp roCl
21 4-CN H H CH~ T
2Z 4-Br H H CH3 H
23 4-J H H 3
24 3-CH3 5-CH3 H CH3 H
4-oCH3 H H Cl H
26 2-CH3 4-oCH3 H Cl H
27 2-C1 4-Br 5-Cl Cl Cl
28 4-oCH3 H H Cl Cl
29 2-CH3 3-OCH3 4-oCH3 Cl H
2-CH3 4-Cl H Cl Cl
31 4-CH(CH3)2 H H Cl H
32 2-CH3 4-oC2H5 H CH3
33 4-OC3~7 H H Cl Cl
34 3-CF3 H H Cl Cl
2-C1 4-Br 5-Cl H Cl
36 4-Cl H H Cl H
37 4-Cl H H CH H
3a 3-C1 5-Cl H Cri 3
39 2-F H H CH~ t!
2-~
41 2-CI-~3 tl H CH~ H
42 3-CH3 H H CH~ ~T
126~7i~
- 12 -
P ration of the end roducts of formula I
re~a P
Example 1
2-Chloro-3- henoxv-6-nitroaniline
P
173 9 of 2-chloro-4-nitro-1,3-diphenoxybenzene
(crude product according to Example ~a)) are dissolved
in S00 ml of triethylene glycol. At 165C, ammonia
is passed through the solution for 6 hours. Thin
layer chromatography then shows that none of the
starting product remains. Whilst the solution is
cooled with ice, 250 ml of 2N sodium hydroxide solution
and 300 ml of water are added. The reaction product
is precipitated and is then suction filtered. 95%
of theory of crude product is obtained, which is
shown by gas chromatography to contain 95.8~ of the
title compound. The total yield over both steps
is 95.3% of theory, m.p. 81-82C (from isopropyl
alcohol).
The same result is achieved using diethylene
glycol or diethylene glycol monobutyl ether as the
solvent instead of triethylene glycol.
In the case of less volatile or more reactive
amines, it is sufficient if the components are reacted
at temperatures of between ambient temperature and
about 160C.
Example 2
2-Methyl-6-nitro-3-phenoxy-N-methylaniline
N~C~I3
~0~ ~
32.1 9 (0.1 mol) of 3-methyl-2,4-diphenoxynitro-
~6~L76~
- 13 -
benzene are dissolved in 100 ml of diethylene glycol.
Methyl amine is slowly introduced into the solution,
with stirring, at 100C. The progress of thè reaction
is monitored by thin layer chromatography (ready-
made TLC plates made by Merck of Darmstadt, silica
gel 60 F254, toluene/heptan 1:1).
After 3L hours the reaction has ended. After
cooling, the product is precipitated by the addition
of 2N sodium hydroxide, with trituration, then suction
filtered and washed with water. Yellow solid; m.p.
60-62C.
Yield: 23 g (89.2% of theory)
` 2~763
-- 14 --
~ ~ r-~
Ov a~ ~ ) ~ ~
CW~
D
O xN c~ ~ ~ ~ r
O
~ I X~ ~ ~ V ~: ~
' q q q q q
~ ~ ~ ~.C X ~: ~ r~
C~
~r: ~ ~ ~ J ;~
. r I r~ r ~ rl rl
~O~ _ ~ L~ r ~ X ~~l r I X
~I H
O
a
Ll ~ r~ J ~ O C- 0 a~, o ~
~_ - 15 -
O D D 1` 0 J N
($~ D
N N N N N3~N V V ~ _,~ ~\ ~T ~
X 3:: X ~ C ) X 3:~
'X C~ V ~ V V C~
~ 5 X ~ X ~ X r~
X rI~
r ~ rr~
r~ 1;~ r~ t ~ t rr~ ~J ,r~ --t N
~ r-l r-l r-l r-lr~l ~I r-l r I N' N N N t~' N
X
763
-- 16 --
~_
o o~ ~ ~ C ~ O
._ I .i I I I ~ I
~O 0 ," ~ 0 ~ 0
1~ ~ 0 r i a:
O
L~
X~
~ ~ ~ W ~ ~ ~ ~ X ~:~ V
X ~ ~ V V ~ v ~ c~ V ~ ::C ~ X
~ ~ "~
X V C~ C~ V V C~ ~ V V V V V V V V C~ V
~-~
r~
_ ~ ~ J ~ ~ ~t ~ X ~~C X ~ ~ ~\U~
V C~ ~ V t~ r
I O
O
~ ~O ~, 0 tJ~ Or t~ t~ ~ t~ t~ ~ C() ~<~ _t ~ -t
F~
- 1 7 -` ~L26~63
U~
C~ O Lr~ ~1
o ~ ~ o~ ~ ~t~
`t I I o I I t~\
O N t~ ~0 Ir~ ~~t--1 r~ (\1 (~ 15~ 0~ tD ~t
N C~ ~/ .a~ 0 N
O ~ O O O O O
~ t~
~J r~ I X
a~ 1 4 I~r4 X ~ ~ ~ 4 ~ C~
N
X~: X, ~ C ~ ~ ~ X X ~ ~ ~ ~ ~'
t~ t ~ t~ t ~ t-~ t~ t~ ,~, t-~t ~ ~ ~ t~ t1
~~.4 ~.4 ~ 4 X X ~ ~ ~ I; 3 ~ I T X ~ ~ ~ X
--
_ ~ ~ X4 ~ X X X
~ N
~ o
~4 1_ X 3 ~ ~4 ~ S\ t ~4 1--4
~<~
~t~ ~t~ r
W I~ -4 ~ r.
O ~C.) t~ C) C.) C_) C.)~.~ ~'t~ ) r_ C~ C~
~ r~ \I r.~J N r~ 4
a
t- ~ ~ ~ ~O ~ 0 ~ O ~ t~ C~ r.
t~ ~ ~ ~ ~ ~ ~ ~ ~ t.~ ~r~ lr~
~c
r~
~L2~763
- 18
, ~
O ~ O N 0 0 ~ t C N ~ X
OO^O^O^O^ OOOOOyOOOO ~
~r
N ~ N O
D ~ ~ X~ N ~0
C C~ V ~ ~
~8
X ~ ~ ~ C ~ -- ::C.,C~C~4 ~ X ~ ~ ~C 3:: ~ h
~e ~
X V ~ VC.) C.) C,)C C U ~ C ~ ~ ~~ . ~
~a~
~ l C ~ C XC~C ~X W l C ~ C ~ C l C ~ C ~ ~\ X
a) ~ ~
,~ a
. .
-IW-~ ~ ~
C~ ~ ~ O
X ~ C~ C ~ C wCW ~ C ~ W W rl J
tU fd
r. r' ~1 o 1 ~ rl c~ r,l vl ~I cl ~ r~
f~ w~ ~ J J N t~ ~ ~,;t ~t J J~t ;t N ,1 0
r~ ,~
fV O ~I N t~ J ~ ~ C0 C~O rl ~`Jr~ J ~ *
r~ ~o ~ ~o ~o ~o ~o ~o ~o ~o
r~ .
64~63
-- 19 --
Table ~I
Compounds of formula
Cl l~nIR2
~,~0 _~N02
(The compounds are obtained in the form of oils)
No. R2 RF values 27C
Acetone/
Heptane Toluene
1: 1
1 C2HS 0.51 0.46
2 n-C3H7 0.615 0.47
3 i-C3H7 0.61 0.45
4 n-C4H9 0.625 0,50
i-C4H9 0.60 0.51
6 HO-CH2-CH2 0.445 0.01
7 CH( 2 5)2
8 -CH2-C-CH 0.31
* 5 toluene/cyclohexan~
~2~ 63
- 20 -
Table III
Compounds of formula
Cl NHR2
C:l _~Q_~ N02
No. R2 X2 Properties/m.p.
1 CH3 Cl red crystals m.p. 101C
C H Cl light brown oil,
2 2 5 uniform according
to thin layer
chromatography
3 i-C3H7 Cl m p. 83C
Cl orange oil, uniform
4 n-C4Hg according to thin
layer chromatography
n C12 25 Cl m p. 43~C
6 n C18 37 Cl 47 - 48C
7 -cH2-cH2-oH Cl dark oil
8 -CH~C2H5)2 Cl
CH =CH-CH H Rf 0.51 (ready-made
2 silica gel TLC plates,
6n F~5~, eluant toluene
CH~C2H5)2
~26~ii3
- 21 -
Table IV
From 1,3-diphenoxybenzenes of formula
Cl O ~ Rl
R ~ O ~ )/ _ NO2
wherein Rl has the meaning given below, the following
compounds of formula
Cl NH-R2
- Rl ~ O _'<~ NO 2
are prepared:
No. Rl R2 Rf values 27C
Acetone Toluene
~ Heptane
1 CH3 C~13 0.61 0.~5
2 CH3 C~l2~1~ 0.63 0.515
3 OCH3 n C3H7 0.29
