US2656354A - Preparation of heterocyclic sulfonic acids - Google Patents

Description

Patented Oct. 20, 1953 PREPARATION OF HETEROCYCLIC SULFONIC ACIDS Roger A. Mathes and Floyd 1). Stewart, Akron, Ohio, assignors to The B. F. Goodrich Company, New York, N. Y., a corporation of New York No Drawing. Application October 14, 1949, Serial No. 121,456

8 Claims. (01. goo-24s) This invention relates to nitrogen-containing heterocyclic sulfonic acids and more specifically pertains to a new and unique method of preparing such sulfonic acids by the oxidation of the corresponding nitrogen-containing heterocyclic thiolsp It has been reported (U. S. Patent No. 2,018,813) that arylene thiazoleand arylene oxazole-2-su1fonic acids can be prepared by oxidizing the corresponding Z-mercapto thiazole or oxazole in the presence of an alkaline medium using sodium hypochlorite hydrogen peroxide, or potassium permanganate as oxidizing agent. It has also been reported that 4-methylthiazole-2- sulfonic acid can be prepared by a similar oxidation of 2-mercapto-4-methylthiazole [J Phar. Soc. Japan 58, 1025 (1938)].

In U. S. Patent No. 2,307,624 it has been disclosed that the reaction of a thiol with nitrogen tetroxide results in the formation of a thionitrate. For example, when nitrogen tetroxide is reacted with tertiary butyl thiol, tertiary butyl thionitrite is formed.

We have now discovered that nitrogen-containing heterocyclic sulfonic acids can, be prepared in excellent yields by oxidizing the corresponding nitrogen-containing heterocyclic thiols with nitrogen tetroxide. It is quite surprising that this reaction should occur in view of the reference hereinbefore cited which discloses that thionitrites are formed by reaction of a thiol with I nitrogen tetroxide. Also, the reaction of this invention is unusual in that no disulfide of the heterocyclic thiol is formed. Nitrogen-containing heterocyclic thiols oxidize readily under most conditions to form their disulfides.

In the practice of this invention any nitrogencontaining heterocyclic thiol (mercaptan) having the formula A--SH wherein A is a nitrogen-containing heterocyclic radical having its connecting valence on a ring carbon atom also attached to a ring nitrogen atom, is oxidized with nitrogen tetroxide to the corresponding heterocyclic sulfonic acid. Examples of the heterocyclic mercaptans which may be employed in the process of this invention include mercapto-thiazoles, mercapto-oxazoles, mercapto-thiazones, mercaptooxazines, mercapto-oxazolines, mercapto-thiazolines, mercapto-quinolines, mercapto thiadiazoles, mercapto quinazolines, mercapto pyrimidines, mercapto thiazolidines and any other heterocyclic compounds containing the characteristic structure wherein X represents bivalent structure preferably free from oxidizable groups, such as hydrocarbon radicals, and radicals composed of carbon, hydrogen and additional hetero atoms which are oxygen, sulfur or nitrogen atoms andlwhich are connected only to carbon atoms. Specific compounds which can be oxidized with nitrogen tetroxide to the corresponding sulfonic acids include 2-mercapto thiazole, Z-mercapto 4,5-dimethyl thiazole, Z-mercapto 4-ethyl thiazole, 2-mercapto-4-methyl thiazole, rhodanine, 2- mercapto benzothiazole, 2-mercapto nitrobenzothiazole, 2-mercapto hydroxy-benzothiazole, 2- mercapto 4-methyl-5-phenyl oxazole, 2-mercapto benzo-oxazole, 2-mercapto thiadiazole, 4,4,6-trimethyl 2-mercapto thiazine, 4-ethyl-5-butyloxazoline, 4-mercapto quinazoline, 2-mercapto quinoline, and 2-mercapto-4,6,6-trimethyl-3-0- tolyl-pyrimidine. I. The conditions for carrying out the above-described oxidation process are quite simple. Since nitrogen tetroxide is a gas at ordinary room temperature it is desirable when using an open reactor to carry out the reaction below room temperature to prevent loss of the oxidizing agent throughevaporation. When the nitrogen oxide is added to the reactor as a gas, it is desirable to employ a closed reactor. Best results are obtained when the oxidation of the heterocylic mercaptans with nitrogen tetroxide is carried out at 0 C. to 10 C. but the oxidation will take place at higher or lower temperatures.

' To achieve the best contact between the nitrogen-containing heterocylic mercaptan and nitrogen tetroxide, the reaction is preferably carried out in the presence of an inert liquid solvent or diluent. Many liquids which are solvents for the heterocyclic mercaptan and which are inert to nitrogen tetroxide are suitable. However, chlorinated hydrocarbons and particularly chloroform and ethylene dichloride have been found to be the most desirable reaction diluents. It is not essential that a reaction diluent be employed, for a mixture of the heterocyclic mercaptan, 0rdinarily a solid, and liquid nitrogen tetroxide can be stirred together at a temperature below 20 C. and the desired heterocyclic sulfonic acid will be i'ormed. The quantities of reactants employed can be varied widely and are not critical. It is ordinarily preferable to use an excess of nitrogen tetroxide over that theoretically required to oxidize the heterocyclic mercaptan in order to insure substantially complete oxidation, *but equimolecular quantities of the mercaptan and of nitrogen tetroxide may be used if desired.

The following specific examples are given to illustrate our new method of preparing heterocyclic sulfonic acids. All parts recited therein are parts by weight.

Example I A solution containing 72.5 parts of 2-mercapto-4,5-dimethylthiazole dissolved in 740 parts of chloroform were added to a reactor fitted with a stirring device, a gas inlet tube entering below the liquid surface, a reflux condenser, and 10 was maintained. A reaction took place during the addition of the nitrogen tetroxide and a material was precipitated to form a slurry. The slurry was stirred for about an hour after the addition of the nitrogen tetroxide was complete and the slurry was warmed to about 25 C. Nitrogen was then bubbled through the slurry to flush out the nitrogen oxide vapors present. The slurry was filtered to recover the precipitate formed during the reaction and the chloroform solution was evaporated to recover a second drop of crystalline material. In this manner 74 parts of white, water-soluble crystals were recovered. The crystalline material after two recrystallizations from ethanol had a melting point of 278 C. and when dissolved in water formed an acidic solution. A chemical analysis of this purified material gave a percentage composition as follows: carbon, 31.16%; hydrogen, 3.76%; nitrogen, 7.25%; sulfur, 33.17%; and oxygen (by difference) 24.66%. This is in agreement with the calculated percentage composition for 4,5-dimethylthiazole-2-sulfonic acid; carbon, 31.12%; hydrogen, 3.62%; nitrogen, 7.25%; sulfur, 33.10%; and oxygen, 24.91%. Hence the white crystalline product obtained was 4,5-dimethylthiazole-Z-sulfonic acid.

Example II A solution containing 81 parts of 4-mercaptoquinazoline dissolved in 740 parts of chloroform was added to the reactor described in Example I. This solution was stirred and cooled to about C. to C. and maintained at this temperature. 53 parts of nitrogen tetroxide were slowly added and a crystalline material was precipitated. The resulting slurry was stirred for about one hour while the slurry wa warmed to room temperature. The reaction vessel was flushed with nitrogen as. before. The slurry was filtered to recover the solid product and an additional crop of crystals were recovered by evaporating the chloroform. In this manner, 84 parts of a yellow crystalline product, soluble in water and giving a strongly acidic aqueous solution, and having a melting point above 320 C. was recovered. This product was determined to be quinazolinel-sulionic acid.

Example III A solution containing 119 parts of 2-mercaptothiazoline dissolved in 740 parts of chloroform was added to the reactor described in Example I. This solution was stirred and cooled to 0 to 5 C. and 110 parts of nitrogen tetroxide were slowly added while a reaction temperature in the range of 0 C. to 5 C. was maintained. A reaction took place during the addition of the nitrogen tetroxide. The product of the reaction formed as a precipitate. The resulting slurry was stirred for about an. hour after the additlon of the nitrogen tetroxide had been completed and the slurry was slowly warmed to room temperature. The reaction vessel was flushed free of nitrogen oxides with nitrogen. The slurry was filtered to recover the solid product and additional crystalline product was recovered. by evaporating the chloroform. In this manner, 159 parts, a 95% yield, of a white, water-soluble crystalline product having a melting point of 140 C. to 150 C. were recovered. This product was determined to be thiazoline-tZ-sulfonic acid.

Example IV A solution containing 58.5 parts of 2-mercaptothiazole dissolved in 1030 parts of chloroform was added to the reactor described in Example I. This solution was stirred and cooled to about 3 C. and 56 parts of nitrogen tetroxide were slowly added to the stirred solution. A reaction took place during the addition of the nitrogen tetroxide and the reaction temperature was controlled at 3 C. to 8 C. The reaction mixture was stirred for about one hour after the addition of the nitrogen tetroxide while the mixture was slowly warmed to room temperature. The reactor was purged with nitrogen to remove the nitrogen oxides. It was then observed that no solid material had formed. The chloroform 50- lution was withdrawn from the reactor, and the chloroform was evaporated leaving 75 parts of an oily residue. The oily material recovered in this manner was water-soluble giving an acidic aqueous solution. The parts of product recovered represented a 98% yield. This oily prodnot was determined to be thiazole-Z-sulfonic acid.

Example V A solution containing 133 parts of rhodanine dissolved in 890 parts of chloroform were added to a reactor described in Example I. This solution was stirred and cooled to about 0 C. and 106 parts of nitrogen tetroxide were slowly added to the stirred solution. During the addition of nitrogen tetroxide, a reaction took place forming a crystalline solid. After the addition of the tetroxide had been completed, the slurry was stirred for about an hour while warming to room temperature. The reactor was flushed with nitrogen to remove nitrogen oxides. The slurry was removed from the reactor and filtered to recover the solid product. The chloroform was evaporated to recover additional product. In this manner, 138 parts of a water-soluble, yellow rystalline product melting. at. C. was recovered. This product was 4-ketothiazolidine-2-sulfonic acid.

Example VI A solution containing 81.5 parts of 2-mercapto- 4,6,6-trimethyl thiazine dissolved in 740 parts of chloroform was added to the reactor described in Example I. This solution was stirred and cooled to 0 C. and then 56 parts of nitrogen tetroxide were slowly added to the reactor. A reaction began as soon as the nitrogen tetroxide was added as evidenced by a rise in temperature. The reaction temperature was maintained at 0 C. to 10 C. When the reaction had ceased the resulting mixture was stirred and warmed to room temperature. The reactor was purged with nitrogen to remove the nitrogen oxides from the reactor. The mixture remaining in the reactor was drawn off and the chloroform removed by evaporation. In this manner there was recovered 101 parts, a 92% yield, of a viscous brown water-soluble oil, identified as 4,6,6-trimethylthiazine-2-sulfonic acid.

In a similar manner heterocyclic sulfonic acids are secured from the other nitrogen-containing heterocyclic mercaptans disclosed hereinabove. The sulfonic acids of Examples II, III, V and VI are new' compounds and are representative, respectively, of quinazoline sulfonic acids, thiazoline sulfonic acids, thiazolidine sulfonic acids and thiazine sulfonic acids. Such sulfonic acids are useful for a variety of purposes. Besides being useful as intermediates in organic synthesis as in the preparation of dyes and drugs, they possess bactericidal and fungicidal activity, they possess slight retarding effect when present during the sulfur vulcanization of rubbery materials and they are quite active as wetting agents.

For example, to 100 parts of a 1% aqueous solution of thiazoline-2-sulfonic acid (described in Example III), there was added parts of sulfur. The resulting mixture was shaken and in a few seconds the sulfur was wetted and well dispersed. The same amount of sulfur when added to 100 parts of water required vigorous stirring for 5 or more minutes to wet the sulfur.

Having disclosed our invention we claim:

1. The method which comprises reacting in an inert liquid solvent at a temperature below room temperature at least equimolecular portions of nitrogen tetroxide with a heterocyclic mercaptan containing the characteristic structure wherein X is a bivalent organic group free from oxidizable groups, and recovering the resulting heterocyclic sulfonic acid.

2. The method which comprises oxidizing in an inert liquid solvent a mercapto thiazolidine with at least equimolecular proportions of nitrogen tetroxide at a temperature below room temperature and recovering the thiazolidine sulfonic acid thus formed.

3. The method which comprises oxidizing in an inert liquid solvent a mercapto thiazoline with at least equimolecular proportions of nitrogen tetroxide at a temperature below room temperature and recovering the thiazoline sultonic acid thus formed.

4. The method which comprises oxidizing in an inert liquid solvent a mercapto thiazine with at least equimolecular proportions of nitrogen tetroxide at a temperature below room temperature and recovering the thiazine sulfonic acid thus formed.

5. The method which comprises oxidizing rhodanine in an inert liquid solvent with at least equimolecular proportions of nitrogen tetroxide at a temperature below room temperature and recovering the resulting 4-ketothiazolidine-2-sulionic acid thus formed.

6. The method which comprises oxidizing 2- mercapto thiazoline with at least equimolecular proportions of nitrogen tetroxide at a temperature below room temperature and recovering the resulting thiazoline-2-sulfonic acid.

'7. The method which comprises oxidizing 2- mercapto-4,6,G-trimethyl-thiazine in an inert liquid solvent with nitrogen tetroxide at a temperature below room temperature and recovering the resulting 4,6,6-trimethyl-thiazine-2-sulfonic acid.

8. Thiazoline-2-sulfonic acid, a white crystalline, water-soluble compound having a melting point of C. to C.

ROGER A. MATHES. FLOYD D. STEWART.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 563,116 Ziegler June 30, 1896 1,841,442 Herz et a1 Jan. 19, 1932 2,018,813 Schubert et al Oct. 29, 1935 2,298,387 Kenyon et al. Oct. 13, 1942 2,451,549 Gzemski Oct. 19, 1948 2,505,910 Proell et al 'May 2, 1950 FOREIGN PATENTS Number Country Date 128,230 Switzerland Oct. 16, 1928 OTHER REFERENCES Houben: Die Methoden Der. Org. Chem. (3rd ed.), vol. 3, pp. 1246, 1247, 1286 (1943).

Ochiai: J. 'Pharm Soc. Japan 58 (1938), p. 1040- 49. Abstract Chem. Abs. vol. 33 (1939), p. 3791.

Claims (1)

1. THE METHOD WHICH COMPRISES REACTING IN AN INERT LIQUID SOLVENT AT A TEMPERATURE BELOW ROOM TEMPERATURE AT LEAST EQUIMOLECULAR PORTIONS OF NITROGEN TETROXIDE WITH A HETEROCYCLIC MERCAPTAN CONTAINING THE CHARACTERISTIC STRUCTURE