Note: Descriptions are shown in the official language in which they were submitted.
7;~7;~
The present invention relates to novel diphenyl-
amines havlng small alkyl substituents on the amino nitro-
gen, which are useful as intermediates for the preparation
of rodenticidal diphenylamines. One phenyl ring has 2,4-
dinitro-6-trifluoromethyl substitution, and the other is
substituted with no more than one methyl or trifluoromethyl
group.
This invention belongs to the rodenticidal and
- organic chemical arts and provides new intermediates for the
preparation of rodenticides.
Rodenticides have long been the subject of re-
search. Rats and mice carry many diseases, and create havoc
when they share the habitations of mankind. They soil and
contaminate buildings, and destroy buildinss and their
contents by their tunneling and nest building. The animals,
when present in numbers, consume or contaminate great
amounts of food.
Many kinds of rodenticides have been discovered
and many are still in use. Probably the best all round
existing rodenticide is the organic chemical compound,
warfarin. Rodents, however, are developing resistance to
existing rodenticides. The metallic poisons, such as
arsenic and thallium compounds, are used to a degree but are
obviously quite dangerous to people and to useful animals.
Tertiary diphenylamines such as those of this
invention have not previously been known. Secondary di-
phenylamines, however, have previously been known to be
fungicides and insecticides.
X-48~9 -~-
~397372
The present invention provides novel diphenyl-
amine compounds of the formula
qlO2 R1 R2
02N~ j~R3
F3
wherein R represents methyl, ethyl or propyl;
Rl and R2 independently represent hydrogen, me~hyl or tri-
fluoromethyl;
10 R3 represents hydrogen or methyl; ---
provided that no more than one of Rl, R2 and R3 represents a
group other than hydrogen. ~: -
The present invention also provides a process
for preparing novel diphenylamine compounds of formula I
wherein the symbols have the meanings stated above, which
comprises reacting a 2-halo-3,5-dinitrobenzotrifluoride
~ ~ compound of the formula . -
.~ qJOz
~ 20 2~-\ 9_x III
~F3
wherein X i5 halo, with an aniline compound of ~he ormula
,~ ,
~ : R3- ~ ~ ~ NH2 III
., ,
,
X-4869 -3-
~g~37Z
wherein Rl, R2, and R3 are as defined above;
follo~ed by N-alkylating the compound so obtained.
All of the compounds described in this document
will be named as diphenylamines for the sake of consistency,
even though the rules of nomenclature might call for some
compounds to be named otherwise.
All percentages and parts described hereafter
refer to percentages and parts by w~ight, and all tempera- -
tures are on the Celsius scale.
The following exemplary compounds are mentioned
only to assure that the reader fully understands the in-
vention.
N,2-dimethyl-2',4'-dinitro-6'-trifluoromethyl-
diphenylamine
N-ethyl-3-methyl-2',4'-dinitro-6'-trifluoromethyl-
diphenylamine
4-methyl-2',4'-dinitro-N-propyl-6'-trifluoro-
methyldiphenylamine
2-methyl-2',4'-dinitro-N-propyl-6'-trifluoro-
methyldiphenylamine
2,4-dinitro-N-propyl-3',6-bis(trifluoromethyl)di-
phenyla~ine
N-ethyl-Z,4-dinitro-2',6-bis(trifluoromethyl)di-
phenylamine
3-methyl-2',4'-dinitro-N~propyl-6'-tri~luoro-
methyldiphenylamine
N-ethyl-4-methyl-2',4'-dinitro-5'-trifluoromethyl-
diphenylamine
The pre~erred compounds of this invention are N-
methyl-2,4-dinitro-6-trifluoromethyldiphenylamine, N-
X-486g -4-
~L~9737;i~
ethyl-2, 4-dini tro-6-trifluoromethyldiphenylamine, 2,4-
dinitro-N-propyl-6-trifluo~omethyldiphenylamine, N-methyl-
2,4-dinitro-3',6-bis(trifluoromethyl)diphenylamine, and N-
methyl-2,4-dinitro-21,6-bis(trifluoromethyl)diphenylamine.
The compounds of formula I are made by the fol-
lowing process.
NOz ~ ~Z
02 f ~ hal~H~ ~-R3 ~
CF3 . .
O~N~ ~Ra /__
Fs
alkylation --\
.
In the above formula, the term "halo" refers to
any of the four common halogen atoms r of which chlorine and
fluorine are preferred and chlorine is usually the most
convenient.
The individual steps of the above process are not
extraordinary in organic chemistry, and are conducted as a
skilled organic chemist would expect. The coupling re-
actions which join the aniline and benzotrifluoride rings
are most readily carried out at relatively low temperatures
X-48~9 -5-
37~
in the range o~ -20 to 10 in dimethylformamide in the
presence of sodium hydride. Other media are likewise
useful. The reactions may be carried out, for example, in
alkanols such as ethanol, in which solvents the reaction
temperature may be higher, in the range of 10~ to 25.
Other solvents, including ketones such as acetone and methyl
ethyl ketone and ethers including diethyl ether and tetra-
hydrofuran, are satisfactory reaction solvents.
In general, a strong base is needed to serve as
acid scavenger. Sodium hydride, as mentioned above, is
generally the most useful base, but other bases including
inorganic bases such as sodium hydroxide and sodium car-
bonate, and organic tertiary amines such as pyridine and
triethylamine, as well as a simple excess of the aniline
starting compound, may be used.
N-Alkylation of the diphenylamines is performed
with reagents such as a dialkyl sulfate or an alkyl halide
in the prPsence of a base. When a dialkyl sulfate is used,
the preferred reaction solvent is acetone. Other solvents,
such as tetrahydrofuran, dioxane and diethyl ether, are also
useful, as are alkanes such as hexane and octane. Dimethyl-
formamide is th~ preferred solvent or alkylations with
alkyl halides, although acetone is also excellent. Other
solvents as described above may ke used.
The preferred bases for use in the alkylation
reactions are those which have a dehydrating effect, parti-
cularly sodium carbonate. However, other inorganic bases,
such as the alkali metal carbonates, bicarbonates and
hydroxides, can be used, as can the alkali metal hydrides.
X-4~69 -6-
3L09737Z
The amount of base used depends upon the reaction
temperature. The higher the reaction temperature in the
alkylation step, the greater excess of base is needed. When
the reaction temperature is approximately ambient, a small
excess of base should be used, such as 2 moles of base per
mole of diphenylamine. When very high reaction temperatures
such as 100 are used, a large excess of base should be
used, in the range of 10-fold.
It will be recognized that it is important to
avoid contamination of the alkylation reaction mixture with
water.
In general, alkylations with dialkyl sulfates are
best performed at about 80~, although temperatures from ap-
proximately room temperature to the reflux temp~rature ma~
be used. Conditions close to room temperature, such as from
20 to 35, are preferred for alkyl halide alkylations, but
elevated temperatures up even to as high as 150 may be
used.
The starting substituted anilines and phenyl
halides are readily obtained by methods which are commonly
known in the chemical literature.
The trifluoromethyl-substituted anilines are best
prepared, as chemists will recognize, by first obtaining a
carboxylic acid-substituted aniline having the acid groups
at the locations of the desired trifluoromethyls. The acid
group is fluorinated with sulfur tetrafluoride.
The following examples, showing the preparation of
typical compounds o~ formula I, are presented to assure that
organic chemists can easily obtain any desired compound.
X-486g _7_
~7372
The products of the examples were identified by nuclear
magnetic resonance analysis, elemental microanalysis,
thin~layer chromatography, and in some instances, by mass
spectrophotometry and infrared analysis.
Example 1
N-methyl-2,4-dinitro-6-trifluoromethyldiphenylamine
A 27 g. portion of 2-chloro-3,5-dinitro~enzotri-
fluoride was added to 20 g. of aniline and 75 ml. of ethanol.
After brief stirring at room temperature, the reaction
mixture was seeded with a small sample of the desired in-
termediate product, and a precipitate formed immediately.
The precipitate was separated by filtration and identified
as 28.5 g. of 2,4-dinitro-6-trifluoromethyldiphenylamine.
The intermediate product was N-methylated in two
different ways, ~oth of which will be shown for tha sake of
clarity.
A. A 3.3 g. portion of the intermediate diphenyl-
amine was taken up in 15 ml. of dimethylformamide, and 1O3
g. of sodium hydride was added. The mixture was stirred at
room temperature, and l.S ml. of methyl iodide was added
with the evolution of heat~ After 1-1/2 hours, another 2
ml. of methyl lodide was added, and the mixture was warmed
slightly. After 2 hours more, the reaction mixture was
added to a large amount of cold water, and the aqueous layer
was decanted. The remaining oil was taken up in diethyl
ether and stirred with magnesium sulfate and charcoal.
After the solids were filtered away, the solution was
evaporated to dryness to produce 2.4 g. of a dark red oil,
which solidified upon cooling. The solid was heated with
X-4869 -8-
37~
petroleum ether, cooled and filtered to produce 2.4 g. of
N-methyl-2,4-dinitro-6-trifluoromethyldiphenylaminé, m.p.
84-86.
TheoreticalFound
C49.28% 49.24%
H 2.95 3.05
N 12.31 12.31
B. Eleven g. of the intermediate diphenylamine
was combined with 45 ml. of dioxane, 14 g. of sodium car-
bonate and 6 ml. of dimethyl sulfate and stirred at refluxtemperature for 24 hours. Twelve ml. of additional dimethyl
sulfate and lO g. of sodium carbonate were then added, and
the mixture was stirred at reflux temperature for 2 hours
more. It was then poured into water and stirred for 4
hours. The aqueous layer was then decanted and the residue
was taken up in methylene chloride and filtered. The solute
was identified as approximately lO g. of crude N-methyl-
2,4-dinitro-6-trifluoromethyldiphenylamine.
Example 2
-
2,4-dinitro-N-~ro~y~6 trlfluorometh~ldiphen~lamine
A 5 g. portion of the diphenylamine intermediate
prepared in the first step of Example l was alkylated with
propyl iodide in 80 ml. of dimethylformamide in the presence
of 20 g. of sodium carbonate. The reaction mixture was
stirred at 110 for 72 hours. The product was recovered by
quenching the reaction mixture with water, extracting with
methylene chloride, and evaporating the solvent under
vacuum. Purification of the crude product on a silica gel
chromatographic column, eluting with toluene, produced 1.2
X-4869 -9-
~09~3~2
g. of pure product, a liquid, NMR peaks at 0.93 (triplet),
1.35-2.05, 3.59, 6.45-6.78, 6.82-7.38, 8.63 and 8.76 ppm.
Example _
N-methyl-2,4-dinitro-2',6-bis(triEluoromethyl)diphenylamine
Following the general process of Example 1, 4.8 g.
of 2-aminobenzotrifluoride was coupled with 8.1 g. of 2-
chloro-3,5-dinitrobenzotrifluoride to produce 4.5 g. of
2,4-dinitro-2',6-bis(trifluoromethyl)diphenylamine, after
purification over a silica gel column with methylene chloride
as the eluting solventO
A 2 g. portion of the above intermediate was
alkylated with 5 ml. of dimethyl sulfate in acetone in the
presence of sodium carbonate. The product was recrystal-
lized from ethanol to produce 75 mg. of N-methyl-2,4-di-
nitro-2',6-bis(trifluoromethyl)diphenylamine, m.p. 148-
149C
Theoretical Found
C4~.02% 43.73%
H 2.22 2.26
N 10.27 lO.09
Example 4
-
N,4-dimethyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine
A 10 g. portion of p-toluidine was coupled with
12.6 g. of 2-chloro-3,5-dinitrobenzotrifluoride in ethanol
according to the general process of Example 1. The inter-
mediate product was recovered by filtration and identified
as 10.1 g. of 4-methyl-2',4'-dinitro-6'-trifluoromethyldi-
phenylamine.
X-48~9 -10-
- .
~9~ 7Z
A 1 g. portion of the above intermediate was
alkylated with 5 ml. of methyl iodide in 12 ml. of acetone
in the presence of 5 g. of sodium carbonate. The mixture
was stirred at reflux temperature for 96 hours. The mixture
was then evaporated to dryness and the residue was digested
with two 150-ml. portions of hot hexane. The hexane was
filtered hot, and the filtrate was evaporated to dryness
under vacuum. The residue was recrystallized from ethanol
to produce 750 mg. of N,4-dimethyl-2',4'-dinitro-6'-tri-
fluoromethyldiphenylamine, m.p. 124-125.
Theo~eticalFound -
C 50.71% 50.51
H 3.40 3.35
N 11.83 11.75
Example 5
N-methyl-2,4-dinitro-3',6-bis(trifluorom~yl)diphenylamine
Twenty g. of 3-aminobenzotrifluoride was coupled
with 16.8 g. of 2-chloro-3,5-dinitrobenzotrifluoride in 200
ml. of anhydrous ethanol at reflux temperature overnight.
The ethanol was then removed under vacuum and the product
was separated from the hydrochloride salt byproduct by
dissolving it in toluene~ The toluene was then evaporated
under vacuum and the intermediate product was recrystallized
from ethanol to produce about 13 g. of 2,4-dinitro-3',6-
bis(trifluoromethyl)diphenylamine, m.p. 99-100.
A 4 g. portion of the above intermediate was then
alkylated with 10 ml. of dimethyl sulfate in acetone in the
X-4869 -11-
~737;~
presence of sodium carbonate according to the process of
.
Example lB. The product was recrystallized from ethanol to
collect 2 g. of N-methyl-2,4-dinitro-3',6-bis(trifluoro-
methyl)diphenylamine, m.p. 108-109.
Theoretical Found
C 44.02% 44.01%
H 2.22 2.35
N 10.27 10.23
Example 6
N,2-dimethyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine
Fifteen g. of o-toluidine was coupled with 18.9 g.
of 2-chloro-3,5-dinitrobenzotrifluoride in 150 ml. of
e~hanol at reflux temperature overnight. A precipitate
formed when the mixture was cooled. The precipitate was
collected and identified as 6.8 g~ of 2-methyl-2',4' di-
nitro-6'-trifluoromethyldiphenylamine.
The above intermediate was alkylated with 20 ml.
of dimethyl sulfate in 25 ml. of acetone in the presence of
12 g. of sodium carbonate. The mixture was held at reflux
temperature for 24 hours, and was then diluted with 50 ml.
of water. The aqueous layer was decanted and the residue
was taken up in methylene chloride, washed with water,
filtered, and evaporated to dryness~ The residue left after
evaporating was purified by chromatography on a silica gel
column with 1:1 pentane:methylene chloride as the eluting
solvent. Four g. of pure N,2-dimethyl-2',4'-dinitro-6'-
trifluoromethyldiphenylamine, m.p. 106-108, was collected.
X-4869 -12-
737Z
Theoretical Found
C 50.71% 50.88%
H 3.40 3.46
N 11.83 12.08
The intermediates of formula I are used in the
preparation of an important series o~ rodenticides by
halogenating or nitrating the aniline ring appropriately.
Th~ reactions follow the usual practice of organic ch~mistry.
For example, halogenations are usually best per-
formed with the elemental hal~gen in acetic acid, or in
methylene chloride or the like halogenated solvent~ in-
cluding chloroform or carbon tetrachloride. ~oom temper-
ature halogenation is usually effective, but increased speed
of reaction i5 obtainable by slight elevation of the re-
action temperature in the range of 25-50. Chlorination is
best done with the elemental gaseous halogen, but bromina-
tion may be done with such agents as N-bromosuccinimide and
dibromoisocyanuric acid, although reaction with elemental
bromine is usually quite satisfac ory.
Iodination is best carried out with iodine mono-
chloride as the reagent.
When a compound having no 4-substituent is to be
made, it will often be necessary to block the 4-position
before halogenating. It is most convenient to use a sul-
fonic acid as the blocking group, because it is readily
added and readily removed.
Insertion of nitro groups on the aniline ring is
readily accomplished with concentrated nitric acid in acetic
acid solution at room temperature. Other nitration re-
X-4~6~ -13-
737Z
actions may also be used, such as a mixture of concentrated
nitric and sulfuric acids at elevated temperatures. In
general, no solvent is used in nitration reactions other
than the acids themselves.
X-~69 -14-
