Note: Descriptions are shown in the official language in which they were submitted.
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Case 5489
TRIFLUOROMETHYL~TION PROCESS
This invention relates to trifluoromethylaromatic
compounds and more particularly to a process for preparing
them.
As disclosed in Matsui et al., Chemistry Letters,
1981, pp. 1719-1720, it is known that aromatic iodides can
be trifluoromethylated by reacting them with a large
excess of sodium trifluoroacetate in the presence of
cuprous iodide and a dipolar aprotic solvent. Matsui et
al. also show that some trifluoromethylation occurs when
an aromatic bromide is employed in the reaction instead of
an iodide but that the yield of product is quite low.
United States patent 4,590,010 (Ramachandran et
al.) teaches that the technique of Matsui et al. is
applicable to the trifluoromethylation of 6-alkoxy-5-
halo-l-cyanonaphthalenes and the corresponding naphthoate
esters -- compounds which, like the compounds of Matsui et
al., give better yields of the desired products when the
halo substituent is iodo. Ramachandran et al. indicate
that other trifluoroacetate salts can be used in their
process, but they disclose a preference for using sodium
trifluoroacetate as the trifluoromethylating agent.
It has been found that the use of sodium tri-
fluoroacetate as a trifluoromethylating agent has several
" J.~
disadvantages. As mentioned above, sodium trifluoro-
acetate has to be used in considerable excess, and it does
not provide acceptable yields of product from aromatic
bromides. Moreover, its use requires a longer reaction
time than would be desired, and it leads to the formation
of relatively large amounts of by-products.
An object of this invention is to provide a novel
process for preparing trifluoromethylaromatic compounds.
Another object is to provide such a process wherein
10 the trifluoromethylaromatic compounds can be prepared in
high yields from aromatic iodides or aromatic bromides.
A further object is to provide such a process which
utilizes a trifluoromethylating agent that is more
selective than sodium trifluoroacetate, can be used in
15 smaller amounts, and does not require as long a reaction
time.
These and other objects are attained by reacting an
aromatic bromide or iodide with potassium trifluoroacetate
in the presence of cuprous iodide and a dipolar aprotic
20 solvent.
Aromatic halides utilizable in the practice of the
invention are substituted and unsubstituted aromatic
iodides and bromides wherein any substituents are inert
substituents (i.e., substituents that do not prevent the
25 reaction from occurring) such as alkyl, alkoxy, alkylthio,
- aryl, aryloxy, arylthio, cyano, nitro, acylamino, alkyl-
amino, tertiary amino, sulfonamido, sulfone, sulfonyl,
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phosphino, perfluoroalkyl, chloro, fluoro, ester, alde-
hyde, ketone, acetal, and sulfono groups. The aromatic
ring may be a carbocyclic ring such as a benzene,
naphthalene or anthracene ring or a five- or six-
membered heterocyclic ring having aromatic character,e.g., a pyridine, quinoline, isoquinoline, thiophene,
pyrrole, or furan ring. Exemplary of such compounds are
iodobenzene, 3-iodotoluene, 4-chloroiodobenzene, 4-
iodomethoxybenzene, l-iodonaphthalene, 3-iodoaniline,
l-iodo-3-nitrobenzene, 2-iodothiophene, 4-iodoiso-
quinoline, 2 iodopyridine, 3-iodoquinoline, and the
corresponding bromides.
In a preferred embodiment of the invention, the
aromatic halide is a halonaphthalene corresponding to the
formula:
Q
R ~
x R'm
wherein R and R' are independently selected from chloro,
fluoro, nitro, hydroxy, and alkyl and alkoxy substituents
containing 1-6 carbons; Q is -CN or -COOR"; R" is satu-
rated hydrocarbyl; X is bromo or iodo; and m is 0 or 1.
The halocyanonaphthalenes and halonaphthoates
utilizable in the practice of the invention may be any
compounds corresponding to the above halonaphthalene
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-- 4
~ormula, but they are pre~erably compounds wherein m is 0,
X is in the 5 position, and ~ is an alkyl or alkoxy
substituent in the 6-position. When the R and R' suh-
stituents are alkyl or alkoxy, they are generally
5 straight-chain groups of 1-3 carbons or branched-chain
groups of three or four carbons, such as methyl, ethyl,
propyl, l-methylethyl, butyl, 2-methylpropyl, 1,1 dimethyl-
ethyl, and the corresponding alkoxy groups, although, as
indicated above, larger groups such as hexyl and hexanoxy
lO are also utilizable. When the halonaphthalene is an
ester, R" may be any saturated hydrocarbyl group (i.e., a
hydrocarbyl group that is ~ree of aliphatic unsaturation)
but is preferably an alkyl, cycloalkyl, aryl, alkaryl, or
aralkyl group containing 1-10 carbons, e.g., methyl,
15 ethyl, propyl, cyclohexyl, phenyl, tolyl, and benzyl.
Particularly preferred halonaphthalenes are 6-alkoxy-
5-bromo-1-cyanonaphthalenes, 6-alkoxy-5-iodo-1-cyano-
naphthalenes, 6-alkoxy-5-bromo-1-naphthoates, and
6-alkoxy-5-iodo-1-naphthoates, especially those compounds
20 ~herein the alkoxy groups are methoxy.
The halonaphthoates are known compounds. The
halocyanonaphthalenes are compounds that can be prepared
by cyanating the appropriately substituted tetralone,
e.g., 6-methoxytetralone, to ~orm the appropriately
25 substituted 1-cyano-3,4-dihydronaphthalene, e.g., 6-
- methoxy-1-cyano-3,4-dihydronaphthalene, aromatizing the
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product in any suitable manner, and brominating or
iodinating the esultant substituted 1-cyanonaphthalene by
known techniques.
The amount of potassium trifluoroacetate reacted
5 with the aromatic halide is not critical and may be a
considerable excess, such as the amounts of sodium
trifluoroacetate that have been employed in the past.
However, since such large amounts of potassium tri-
fluoroacetate are not required, the amount used is gen-
10 erally in the range of 1-3 equivalents, most commonly
1.5-2 equivalents.
Dipolar aprotic solvents that may be utilized
include, e.g., N-methylpyrrolidone, N,N-dimethylformamide,
N,N-dimethylacetamide, hexamethylphosphoric triamide, and
15 dimethylsulfoxide. The particular solvent employed does
not appear to be critical except in the sense that it
should have an appropriate boiling point for use at the
reaction temperatures to be utilized, but the preferred
solvents are N,N-dimethylformamide and N,N-dimethyl-
20 acetamide. The solvent is used in solvent amounts, e.g.,an amount such as to provide an organic solids concen-
tration of up to about 15%~
The cuprous iodide may be employed in any suit-
able amount, generally an amount in the range of 0.5-5
25 equivalents.
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The reaction is conducted by combininy the ingre~dients in any convenient order and heating them at a
suitable temperature, for example, reflux temperature, to
accomplish the desired trifluoromethylation. Anhydrous
conditions are preferably employed, an~ the temperature is
generally in the range of 130-160C., preferably
1~0-155C.
After completion of the reaction, the product may
be recovered by conventional techniques and/or subjected
to further reactions to form derivatives. For example,
products obtained by trifluoromethylating the preferred
halocyanonaphthalenes and halonaphthoates can be subjected
to reactions such as those taught by Sestanj et al. in
U.S. Patent 4,439,617. Thus, e.g., (1) a (trifluoro-
methyl)cyanonaphthalene or trifluoromethylnaphthoatepreared by the trifluoromethylation reaction may be
hydrolyzed to the corresponding acid in the presence of a
base such as sodium or potassium hydroxide, (2) the acid
can be halogenated, e.g., by reaction with thionyl
chloride, to form the corresponding acid halide, (2) the
acid halide may be reacted with a saturated hydrocarbyl
ester of an acid corresponding to the formula ZNHCH2COOH
(e.g., methyl, ethyl, propyl, cyclohexyl, phenyl, tolyl,
or benzyl sarcosinate, the corresponding esters of amino-
acetic acids having other N-substituents (Z3 containing
~ 1-6 carbons, such as N-ethyl and N-propyl) to form an
amide corresponding to the formula:
~ ,V,~7~
O=c_N(z)_cH2coo
CF3 R'm
and (3) the amide may be thiated, e.g., with phosphorus
pentasulfide or the like, and the product saponified and
hydrolyzed to form a thioamide corresponding to the
formula:
S=C-N(Z)-CH2COOH
/\~
Rt ~1--~
3 R'm
The invention is advantageous in that it permits
trifluoromethylaromatic compounds to be prepared in high
yields from the corresponding aromatic bromides or iodides
at a faster rate and with the use of less reagent than is
required when sodium trifluoroacetate is employed. Also,
the reaction is more selective than the sodium trifluoro-
acetate reaction, so the product is l~ss contaminated with
by-product. Additionally, the potassium trifluoroacetate
reactions can be accomplished with higher concentrations
of solids than are operable when sodium trifluoroacetate
~ is used, and the reactor productivity can thus be in-
creased considerably.
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The following examples are given to illustrate the
invention and are not intended as a limitation thereof.
COMPARATIVE EXAMPLE A
A mixture of one molar proportion of 6-methoxy-
5-iodo-1-cyanonaphthalene (6-MICN), 2.3 molar proportions
of sodium trifluoroacetate, and 1.9 molar proportions of
CuI was stirred into 146 molar proportions of toluene,
after which about 82 molar proportions of the toluene were
stripped at lll~C. Then 83 molar proportions of dry
N,N-dimethylacetamide (DMAC) were added, and the mixture
was heated while distilling over the remainder of the
toluene until the temperature reached 152C. Heating was
stopped, another 0.7 molar proportion of sodium trifluoro-
acetate was added, and the reaction mixture was heated
back up to 152C. and stirred for 80 minutes at 152-155C.
to give a total reaction time of four hours. After
cooling and workup, GC analysis showed the reaction mix-
ture to contain 97.25 area % of the desired 6-methoxy-
5-trifluoromethyl-1-cyanonaphthalene (6-MTCN).
COMPARA~IVE EXAMPLE B
Comparative Example A was essentially repeated
except that the 6-MICN was replaced with 6-methoxy-
5-bromo-1-cyanonaphthalene (6-MBCN) and the total reaction
time was 6 hours. GC analysis of the final reaction
25 mixture showed 93.45 area % of 6-MTCN.
COMPARATIV2 :E:XA~qPLE C
Using the same general procedure as in Comparative
Example A, one molar proportion of methyl 6-methoxy-5-
bromo-1-naphthoate (MMBN) was reacted with 1.7 molar
proportions of sodium trifluoroacetate in the presence of
2 molar proportions of CuI and 46 molar propor'cions of
N,N-dimethylformamide (DMFj, with an additional 0.95 molar
proportion of sodium trifluoroacetate being added during
the course of the reaction. The total reaction time
was 5 hours. After workup, the desir~d methyl 6-methoxy-
5-trifluoromethyl-1-naphthoate (MMTN) was isolatsd in a
76% yield.
COMPARATIVE EXAMPLE D
A mixture of one molar proportion of 4-bromodi-
phenyl ether, 1.99 molar proportions of CuI, and 1.7 molar
proportions of sodium trifluoroacetate was stirred into 14
molar proportions of toluene, after which part of the
toluene was stripped, 46 molar proportions of DMF were
added, and the reaction mixture was heated up to 149C.
for thr~e hours. Heating was stopped, another molar
proportion of sodium trifluoroacetate was added, and the
mixture was heated up to 149C. for two hours. GC analy-
sis of the product showed 47.5 area % of the desired 4-tri-
fluoromethyldiphenyl ether, 26.5 area % of perfluoroalkyl
homologs, and 22.8 area % of unreacted 4-~romodiphenyl
ether.
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EXAMPLE I
A mixture of one molar proportion of 6-MICN, l.g
molar proportions of CuI, and 1.7 molar proportions of
potassium trifluoroacetate was stirred into 10 molar
5 proportions of toluene after which part of the toluene was
stripped, 40 molar proportions of DMF were added, and
toluene and DMF were stripped until the temperature
reached 149C. The temperature was maintained at 149-
150C. for two hours, after which GC analysis showed that
10 all of the 6-MICN had been converted and more than 98% had
been converted
to 6-MTCN.
EXAMPLE II
A mixture of one molar proportion of 6-MBCN, 2
15 molar proportions of CuI, and 1.7 molar proportions of
potassium trifluoroacetate was stirred into 15 molar
proportions of toluene, after which part of the toluene
was stripped and 66 molar proportions of DMF were added.
The reaction mixture was heated at 1~0-150C. for about
20 3.5 hours, cooled, worked up, and subjected to GC
analysis. the analysis showed substantially 100%
conversion to 6-MTCN and a trace formation of by-product.
EXAMPLE III
Example II was essentially repeated except that the
- 25 solids concentration was doubled. Similar results were
observed.
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EXAMPLE IV
Example II was essentially repeated except that the
amount of potassium trifluoroacetate used was 1.5 molar
proportions, and 53 molar proportions of DMF were sub-
5 stituted for the DMAC. The GC analysis showed 99.77 area% of 6-MTCN.
EXAMPLE V
Comparative Example C was essentially repeated
except that the initial sodium trifluoroacetate was
lO replaced with 1.75 molar proportions of potassium tri-
fluoroacetate, no additional trifluoroacetate was added
during the course of the reaction, and the reaction time
was only 3.5 hours. GC analysis showed a conversion of
99.8%, and the isolated yield of product was a6%.
EXAMPLE VI
Comparative Example D was essentially repeated
except that the initial sodium trifluoroacetate was
replaced with 2.69 proportions of potassium trifluoro-
acetate, no additional trifluoroacetate was added during
20 the course of the reaction, and the reaction time was 3.5
hours. GC analysis of the product showed 67 area % of the
desired 4-trifluoromethyldiphenyl ether, 16.6 area % of
perfluoroalkyl homologs, and 16.2 area % of unreacted
4-bromodiphenyl ether.
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It is obvious that many variations may be made in
the products and processes set forth above without
departing from the spirit and scope of this invention.
