Method for converting carboxylic acid groups to trichloromethyl groups

Method for converting carboxylic acid groups to trichloromethyl groups which comprises contacting a compound containing a carboxylic acid group with a phenylphosphonic dichloride and phosphorus pentachloride and recovering the thus produced product.

BACKGROUND OF THE INVENTION 
It is known to convert a ring attached carboxylic acid group to a 
trichloromethyl group when said acid group is on the ring of a nitrogen 
heteroaromatic compound and in a position adjacent to a ring nitrogen 
atom. 
One reason for making such conversions is to allow for the preparation of 
compounds which cannot be prepared by the conventional practice of direct 
chlorination of methyl groups. For example, compounds containing alkoxy, 
alkyl or alkoxy or alkyl substituted aryl groups, in addition to the 
methyl group to be converted, cannot normally be prepared by direct 
chlorination without chlorination of the above groups. 
Most known processes involve treatment of the carboxylic acid compound with 
phosphorus pentachloride usually in the presence of excess thionyl 
chloride. Such processes are taught by Takahashi et al. "Kinetic study on 
the conversion of pyridine and Quinolinecarboxylic acids to the 
corresponding Trichloromethyl Compound," J. Het. Chem. 15 893 (1978); 
Chemical Abstracts 74, 125566y; Chemical Abstracts 79 31986m and Chemical 
Abstracts 81 105395h. Related processes for other types of chlorinations 
are taught in Chemical Abstracts 63 9901d and U.S. Pat. No. 2,907,798. 
Since the known procedures are only useful in the conversion of carboxylic 
acid groups to trichloromethyl groups when the acid group is adjacent to 
the nitrogen atom in a nitrogen heteroaromatic cyclic, it would be 
desirable to find less selective procedures and procedures which can be 
employed with other than nitrogen heteroaromatics. 
SUMMARY OF THE INVENTION 
The present invention is directed to a method for the conversion of 
carboxylic acid groups to trichloromethyl groups which comprises 
contacting an aryl or heteroaryl compound containing a carboxylic acid 
group with a phenylphosphonic dichloride and phosphorus pentachloride. 
More specifically, the present invention is directed to a method for the 
conversion of any carboxylic acid groups on an aryl or heteroaryl ring to 
trichloromethyl groups by reaction thereof with a phenyl phosphonic 
dichloride and phosphorus pentachloride. This reaction can be 
characterized as follows: 
##STR1## 
wherein R represents aryl or N-heteroaryl and n is 1 or 2. (No attempt has 
been made to present a balanced equation.) 
The aryl or N-heteroaryl carboxylic acid compounds useful in the present 
process can be any aryl or N-heteroaryl compound containing one or two 
carboxylic acid groups in non-sterically hindered ring positions and which 
compound is substantially chemically and physically stable under the 
acidic conditions of the reaction with the exception of the conversion of 
the carboxylic acid groups to the corresponding trichloromethyl groups. 
When there are two acid groups present they should be in nonadjacent ring 
positions to avoid steric hindrance problems. 
The compounds can in addition be ring substituted with additional 
sterically compatible groups which are non-reactive under the conditions 
of the reaction such as chloro, fluoro, nitro, cyano, alkyl, alkoxy, 
alkylthio, aryl, alkyl substituted aryl, alkoxy substituted aryl, aryloxy, 
trichloromethyl or trifluoromethyl. To further insure that problems of 
steric hindrance be avoided, it is important that no groups having an atom 
radius larger than the atom radius of a chlorine atom be adjacent to a 
carboxylic acid group. Further, if an alkyl, alkylthio or alkoxy group is 
substituted on an aryl ring, it is necessary that a strong electron 
withdrawing group such as nitro or cyano be also on the ring. This latter 
requirement is not necessary for N-heteroaromatic compounds. 
In the present specification and claims, the term "sterically compatible" 
is employed to designate substituent groups which are not affected by 
steric hindrance as defined in "The Condensed Chemical Dictionary," 7th 
edition, Reinhold Publishing Co. N.Y., page 893 (1966) which definition is 
as follows: 
"steric hindrance. A characteristic of molecular structure in which the 
molecules have a spatial arrangement of their atoms such that a given 
reaction with another molecule is prevented or retarded in rate." 
Steric hindrance may be further defined as compounds having substituents 
whose physical bulk does not require confinement within volumes 
insufficient for the exercise of their normal behavior as discussed in 
"Organic Chemistry" D. J. Cram and G. Hammond, 2nd edition, McGraw-Hill 
Book Company, N.Y., page 215 (1964). 
In carrying out the present process, the order of the addition of the 
reactants is not critical although in some situations, one mixing 
procedure may be more desirable than another. For example, if the reaction 
is to be run on a large scale, it is helpful to allow the carboxylic acid 
compound and the phenyl phosphonic dichloride compound to react for a 
period of time (until HCl evolution ceases) before adding the phosphorus 
pentachloride. This allows for more control of any initial foaming which 
might occur and more control of the exothermic nature of the reaction. In 
other situations, all the reactants can be mixed together. 
After the reactants are mixed, the mixture is heated at reflux, 
.about.100.degree.-.about.250.degree. C. The process is usually carried 
out at atmospheric pressure; however, the reaction goes well at pressures 
of from about 0.1 to about 10 atmospheres. 
The reaction is usually completed in from about 4 hours to about 7 days, 
dependent upon the temperature, reactants and amounts of reactant. Upon 
the completion of the reaction, the reaction mixture is cooled and the 
phosphorus oxychloride byproduct is removed by distillation under reduced 
pressure. The desired product can be separated and recovered by 
conventional techniques such as by fractional distillation under reduced 
pressure or by solvent extraction after the reaction mixture was made 
basic with dilute base. The product can be purified if desired by 
conventional techniques such as by water washing, drying and 
recrystallization from a solvent such as benzene, hexane, methanol, 
chloroform, ether, cyclohexane or acetonitrile. 
The phenylphosphonic dichlorides are usually present in an amount of from 
about 0.1 to about 20 molar equivalents of the phenylphosphonic dichloride 
per carboxylic acid group on the carboxylic acid compound. Preferably, 
from about 1 to about 10 molar equivalents of the phenylphosphonic 
dichloride per carboxylic acid group is employed. 
Representative of those phenylphosphonic dichlorides which can be employed 
in the practice of the present invention include those corresponding to 
the formula 
##STR2## 
wherein X, Y and Z independently represents hydrogen, fluoro, chloro, 
cyano, trifluoromethyl, nitro and alkyl sulfonyl of 1 to 4 carbon atoms. 
The phosphorus pentachloride is usually present in an amount of from about 
2 to about 10 molar equivalents of the phosphorus pentachloride per 
carboxylic acid group on the carboxylic acid compound. Preferably, from 
about 2 to 5 molar equivalents of the phosphorus pentachloride per 
carboxylic acid group is employed. If the carboxylic acid compound is ring 
substituted with a reactive group such as bromo, iodo or hydroxy group, an 
additional molar equivalent of the phosphorus pentachloride is necessary 
for each such group. These reactive groups are normally replaced with 
chlorine.

DESCRIPTION OF SOME PREFERRED EMBODIMENTS 
The following examples illustrate the present invention and the manner by 
which it can be practiced but, as such, should not be construed as 
limitations upon the overall scope of the same. 
EXAMPLE I 
Preparation of 4-chloro-2,6-bis(trichloromethylpyridine). 
##STR3## 
To a 5-liter flask equipped with a mechanical stirrer, thermometer and 
condenser was added 1950 grams (g) (10 moles (m)) of phenylphosphonic 
dichloride. Thereafter 302 g (1.5 m) of 2,6-dicarboxy-4-hydroxypyridine 
monohydrate (chelidamic acid monohydrate) was rapidly added. The mixture 
was slowly and carefully heated to 150.degree. C. over a two hour period. 
Thereafter, the mixture was cooled to 50.degree.-60.degree. C. and 1029 g 
(5.25 m) of phosphorus pentachloride was rapidly added. The mixture was 
heated until the internal temperature was 75.degree.-80.degree. C. and the 
heat source removed. The temperature exothermically rose to 
.about.125.degree. C. and after a short period, the temperature started to 
cool. When the reaction mixture reached a temperature of 90.degree. C., a 
second portion of phosphorus pentachloride (1029 g (5.25 m) was added and 
the mixture heated at reflux (.about.140.degree.-145.degree. C.) for 12 
hours. The condenser was replaced with a distilling head and the reaction 
mixture was distilled and the by-product phosphorus oxychloride was 
distilled off until a pot temperature of 215.degree. C. was reached. At 
this point, the distilling head was replaced with a short fractionating 
column and phenyl phosphonic dichloride was rapidly distilled off at 
75.degree.-85.degree. C. and 0.05 millimeters of mercury (mm Hg). The 
crude 4-chloro-2,6-bis(trichloromethyl)pyridine which remained solidified 
upon standing, and recrystallization of this material from methanol gave 
314 g (60 percent of theoretical). The product melted at 
101.degree.-102.degree. C. and its structure was confirmed by its Nuclear 
Magnetic Resonance spectra (NMR). 
In other runs, this compound was prepared in yields as high as 85 percent 
of theoretical. 
EXAMPLE II 
Preparation of 1-nitro-4-(trichloromethyl)benzene 
##STR4## 
A mixture was prepared by adding with stirring and in the following order, 
16.7 g (0.1 m) of 4-nitrobenzoic acid, 15.7 g (0.11 m) of phenylphosphonic 
dichloride and 52 g (0.25 m) of phosphorus pentachloride. The mixture was 
heated and stirred and within 1 to 2 minutes, vigorous HCl evolution began 
and the mixture became a clear yellow liquid. The reaction mixture was 
heated at reflux for .about.15 hours, cooled to 25.degree. C. and the 
phosphorus oxychloride byproduct was removed by evaporation under reduced 
pressure. The oil which remained as a residue was cautiously poured into a 
10% solution of sodium carbonate in cold water and stirred vigorously 
until foaming ceased while maintaining the temperature below 30.degree. C. 
The resultant solid crude 1-nitro-4-(trichloromethyl)benzene was recovered 
by filtraton, washed with water, air dried and recrystallized from hexane 
to give 19.6 grams (81 percent of theoretical) of product. The product 
melted at 44.degree.-47.degree. C. and its structure was confirmed by NMR. 
In other runs, this compound was prepared in yields as high as 94 percent 
of theoretical. 
EXAMPLE III 
Preparation of 2,3-dichloro-5-(trichloromethyl)pyridine 
##STR5## 
To a 5-liter flask equipped with an air stirrer, thermometer, and condenser 
was added 1000 grams (5.13 m) of phenylphosphonic dichloride. Thereafter, 
383 g (2.707 m) of 5-chloro-6-hydroxynicotinic acid (prepared by bubbling 
chlorine into a stirred aqueous suspension of 6-hydroxynicotinic acid) was 
added. The mixture was slowly heated and stirred over a 20 minute period, 
with the temperature rising to 73.degree. C. The mixture was in the form 
of a thick paste. 
To this mixture was slowly added 1755 g (8.4 m) of phosphorus pentachloride 
over a 45 minute period. The hydrogen chloride by-product which formed was 
continuously removed and the heat was adjusted to maintain the temperature 
in the range of 83.degree.-108.degree. C. After the phosphorus 
pentachloride addition was complete, the mixture was heated to reflux and 
some of the phosphorus oxychloride by-product which formed was allowed to 
distill off. After a period of about 70 minutes, the temperature had 
exothermically risen to 169.degree. C. and the temperature was held in the 
range of 162.degree.-180.degree. C. for 53/4 hours. During the above time 
additional phosphorus oxychloride was intermittently removed. The mixture 
was allowed to stand overnight and then poured over cracked ice, 
neutralized with 50 percent sodium hydroxide solution and the product 
extracted with hexane. The solvent was removed by evaporation under 
reduced pressure leaving 567 g of crude 
2,3-dichloro-5-(trichloromethyl)pyridine. 
The crude product was placed on a 15 tray vacuum jacketed Oldershaw 
distillation column and the light ends removed. The pot material was 
transferred to a Vigreux Claisen still and flash distilled to yield of 518 
g (88.5 percent of theoretical) of a colorless oil which analysed as 99 
percent pure 2,3-dichloro-5-(trichloromethyl)pyridine. Upon analysis the 
product was found to have carbon, hydrogen, chlorine and nitrogen contents 
of 26.99, 0.76, 66.49 and 5.23 percent respectively, as compared with the 
theoretical contents of 27.15, 0.76, 66.81 and 5.28 percent respectively, 
as calculated for the above named compound. 
In Examples I, II and III, no attempt has been made to present balanced and 
complete reaction schemes. 
By following the procedures as outlined in Examples I, II and III, the 
following compounds set forth below in Table I are prepared. 
TABLE I 
______________________________________ 
Yield 
in Per- 
Compound cent Physical Property 
______________________________________ 
##STR6## 81 
##STR7## 
##STR8## 74 
##STR9## 
##STR10## 72 
##STR11## 
##STR12## 94 M.P. = 104.degree.-107.degree. C. 
##STR13## 67 
##STR14## 
##STR15## 57 
##STR16## 
##STR17## 
##STR18## 
##STR19## 75 
##STR20## 
##STR21## 42 
##STR22## 
##STR23## B.P. = 218.degree. C. @ 760 mm 
##STR24## 
##STR25## B.P. = 84.degree.-86.degree. C. @ 1 mm 
##STR26## wt. crystals 
##STR27## M.P. = 82.degree.-84.degree. C. 
##STR28## 85 M.P. = 101.degree.-102.degree. C. 
##STR29## 
##STR30## 82 M.P. = 52.degree.-54.degree. C. 
##STR31## 
##STR32## 81 
##STR33## 
##STR34## 
##STR35## 
##STR36## 
##STR37## 
##STR38## 
##STR39## Yellowish Solid 
##STR40## M.P. = 135.degree.-137.degree. C. 
##STR41## B.P. = 153.degree.-155.degree./3 mm 
##STR42## M.P. = 75.degree.-77.degree. C. 
##STR43## M.P. = 77.degree.-79.5.degree. C. 
##STR44## M.P. = 68.degree.-69.degree. C. 
##STR45## oil 
##STR46## oil 
##STR47## oil 
##STR48## B.P. = 101.degree.-103.degree. C./24 mm 
##STR49## M.P. = 88.degree.-91.degree. C. 
##STR50## M.P. = 33.degree.-35.degree. C. 
##STR51## M.P. = 47.5.degree.-48.degree. C. 
##STR52## M.P. = 56.degree.-58.degree. C. 
##STR53## M.P. = .about.38.degree. C. 
##STR54## B.P. = 100-103/1.5 mm 
##STR55## M.P. = 125.degree.-127.degree. C. 
##STR56## M.P. = 37.degree.-41.degree. C. 
##STR57## B.P. = 113.degree. C./6 mm 
##STR58## M.P. = 65.degree.-68.degree. C. 
##STR59## M.P. = 42.degree.-43.degree. C. 
##STR60## M.P. = 44.degree.-46.degree. C. 
______________________________________ 
STARTING MATERIALS 
The starting materials employed in the process of the present invention are 
known materials, the preparation of which is taught in the literature or 
they are articles of commerce.