US3434944A

US3434944A - Electrolytic process for splitting aromatic carboxylic acid amides and sulfonic acid amides

Info

Publication number: US3434944A
Application number: US471467A
Authority: US
Inventors: Leopold Horner; Heinz Neumann
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1964-07-16
Filing date: 1965-07-12
Publication date: 1969-03-25
Anticipated expiration: 1986-03-25
Also published as: DE1493664A1; DE1493665A1; GB1088484A; NL6509235A; CH456619A; FR1453364A

Description

United States Patent 3,434,944 ELECTROLYTIC PROCESS FOR SPLITTING ARO- MATlC CARBOXYLIC ACID AMIDES AND SUL- FONIC ACID AMIDES Leopold Homer, Mainz-Bretzenheim, and Heinz Neumann, Frankfurt am Main, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Filed July 12, 1965, Ser. No. 471,467 Claims priority, application Germany, July 16, 1964, F 43,449, F 43,450 int. Cl. B01k 1/00 US. Cl. 204-59 2 Claims ABSTRACT OF THE DISCLOSURE A process for reductively cleaving an aromatic carboxylic acid amide or an aromatic sulfonic acid amide into a corresponding amine and aromatic alcohol or aromatic sulfinic acid, respectively, by electrolyzing a solution of said amide in the presence of a tetraalkyl ammonium salt such as tetramethyl ammonium chloride.

It is already known to split carboxylic acid amides with lithium alanate by way of reduction to form alcohols and amines (J. Org. Chem., 18, 1190). The process can, however, be successfully applied only if acid amides derived from weakly basic amines are concerned, the nitrogen atom of which is coupled with a system capable of exhibiting a strong resonance.

It is likewise known to reduce p-toluene-sulfonamides to the corresponding amines by the action of sodium in boiling isoamyl alcohol (Berichte, 86, 1246 (1953)). In this process, the tosyl radical is split into toluene, sulfur dioxide and hydrogen sulfide. The high reaction temperatures and the strongly alkaline medium may, however, unfavorably affect sensitive amines.

Tests for reductively splitting sulfonamides by means of Grignard reagents or by means of lithium-aluminum hydride likewise show unsatisfying results (Monatshefte, 84, 651 (1953);]. Org. Chem, 16, 952 (1951)).

Now we have found that aromatic carboxylic acid amides and sulfonic acid amides can be split under protective conditions by subjecting them in the presence of tetra-alkyl-ammonium salts to electrolytic reduction. The compounds correspond to the general formulae In the above formulae R represents, for instance, a phenyl group, which may be substituted, or a naphthyl group. R and/or R represent, for instance, hydrogen, low-molecular weight alkyl, cycloalkyl with 5 to 8 carbon atoms, a phenyl group which may be substituted by low-molecular weight alkyl, a phenylalkyl group or aralkyl groups, or, together, represent an alkylene group having 3 to 8 carbon atoms which may 'be interrupted by O, N or S. R may likewise be the radical of an amino acid or of a peptide. R may carry further substituents which are not reducible. As such, there are suitable, in particular, low-molecular weight alkyl, phenyl, trifluoromethyl, low-molecular weight alkoxy, lowmolecular weight alkylene-dioxy, carboxy, carbalkoxy, amino and hydroxy groups.

The tetraalkyl-ammonium salts used are derived from inorganic acids such as hydrohalic acids, especially hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid or perchloric acid. Organic acids such as formic acid, acetic acid, propionic acid and higher fatty acids as well as aromatic carboxylic acids, for instance benzoic acids, can likewise be used as salt formers. The tetra-alkyl-ammonium salts contain alkyl groups with up to 4 carbon atoms, preferably tetramethyl-ammonium salts.

The electrolysis is carried out in a vessel in which the anode and cathode are separated by a diaphragm. As material for the anodes, graphite is preferably used, but boron carbide and other carbides may likewise be used. As cathode material, metals are used, in particular mercury, lead, iron and platinum. As solvent, methanol is generally employed. Water or aqueous solutions of appropriate ethers, such as dioxane or tetrahydrofurane are likewise suitable. In order to ensure a rapid course of the reaction and quantitative yields, it is recommendable to add the tetra-alkyl ammonium salt in excess. A proportion of 3 parts of ammonium salt to 1 part of substrate to be split has proved most favorable, but any other proportions may likewise be used with success. The range of the reaction temperature is between 0 and 20 C., preferably between 5 and 10 C. The termination of the reaction is announced by a strong evolution of hydrogen. In order to attain a complete cleavage it is recommended to exceed the theoretically required period by one fourth to one third of the time involved.

In the process of the present invention, amines and aromatic alcohols or aromatic sulfinic acids are simultaneously obtained in high yields. By-products are not formed in the course of the reaction. A possibility for use is, therefore, in the field of peptide synthesis. Since the peptides formed as decomposition products are not racemized or decomposed because of the gentle reaction conditions, the process permits removal of the carbonyl radicals or of the tosyl group used as protective groups in the peptide synthesis in an uncomplicated manner. Furthermore, the process constitutes a practicable method for the preparative production of aromatic sulfinic acids which, otherwise, are obtained with difficulties only.

General instructions 10 millimols of the substrate to be split are subiected to electrolysis together with 30 millimols (3.3 grams) of tetramethylammonium chloride in 35 cc. of methanol. Upon cooling of the reaction mixture of +5 C., an earthenware shell containing the graphite anode and cooling finger is introduced into the vessel. The space between the mercury surface and the bottom of the shell amounts to 0.5 to 1 cm. 1-2 cc. of water are introduced into the anode region. As soon as the electric circuit is closed 18-24 volts) the intensity of the current soon increases. It is maintained constant at l ampere by means of a variable electrical resistance.

If two vessels are connected in series, 40 volts are applied. From time to time the reaction vessel is slightly shaken. About 10 minutes after the evolution of hydrogen has set in, the electrolysis is interrupted, the earthenware shell (tube) is rinsed With a small amount of methanol and the reaction batch is worked up,

Generally, the reduction is carried out at a temperature between C. and C. For working up the reaction mixture, 5 cc. of 2 N-sodium hydroxide solution are added and the amino component is extracted with ether. The amine is precipitated from the ethereal solution in the form of the hydrochloride, and the yield is determined. The following table shows an enumeration of the compounds examined and the yields in split products.

4 The pure starting substance shows a rotation value of The small difference in the specific rotation value is due to slight contamination with sodium chloride and sodium bicarbonate. A rotation value of [a] =--1O.5 is also obtained if the pure starting substance is dissolved in 2 N- hydrochloric acid and precipitated by means of NaHCO Splitting of p-toluenesulfonyl-glycyl-glycine 2.43 grams of p-toluenesulfonyl-glycyl-glycine are subjected to splitting. The electrolytic splitting occurs as de- Carboxylic acid Amine Yield Alcohol Yield scribed above for toluenesulfonyl-tyrosine. At the end of y p qi or Amlinoiticd or littl (l the electrolysis the dipeptide again dissolves due to the in- N'acy'pep 1 9 ep 6 1c creasing alkalinity, Sulfinic acid is obtained in a yield of Bemoyl-DlL'meth BIL-math n 77 92.5% of the theory. The alkaline reaction mixture is Benzoyl-gly-D,L-meth. Gly-D,L-meth 68 1 Benzoyl-gly-D,L-phe Gly-D,L-phe e3 centrated near y to dryness in a rotating evaporator and cc. of absolute alcohol are poured thereon. On

Toluenesulfonamide (tsa) Amine Yield, Sulfinlcacid Yield, percent percent;

N-n-hexyl-tsa n-Hexylamine 93.8 Toluenesulfinic acid 97. 3 N-n-butyl-tsa. n-Butylamine 54.8 96.6 N-cyclohexyl-tsa- Cyclohexylamine. 77.0 95.3 N-benzyl-tsa"..- Benzylamine 64. 4 90. 0 N-phenyltsa Aniline 87.8 87.3 N,Ndipheny1-tsa Diphenylamine 88.3 86.0 N-phenyl-N-benzyl-tsa Benzylaniline 95.5 96.6 N-2,6-dimethylphenyl-tsa 2,6-dimethylanillne 92.1 94.0 2,6diethylaniline 94. 4 94. 4 N-methyl-benzylamin 98. 5 95. 8 2,4,6trimethylaniline" 96. 2 95. 4 p-Toluidine 95. 0 98. O Piperidine 67. 9 91. 0 Benzenesnlfa'nihde Aniline 86. 7 87.0 N-benzyl-benzenesuliamide Benzylamide 67.4 80.0 N-fl-phenylethyl-tsa B-Phenyl-ethylamme 82.5 94.3

neutralization by means of methanolic hydrochloric acid N-tosylaminoacid or Amincaeid or peptide Percent the diglycine precipitates, N'myl'peptlde Yield 1.2 g.=91%. In the mother liquor, only slight Ts-D,L-meth --fiamounts of diglycine can be detected with the aid of thin- 22l2%;1$f 3g layer chromatography. The precipitate is recrystallized gs-glyilL-phei- 33 from a mixture of ethanol and Water (3:2). IZafi; 86 Analysis.-Calculated for (3 11 19 0 132.1 c, 36.36; Ts-gly-DyL'tfy 98 H, 6.1. Found: C, 36.34; H, 6.57.

Ts=t0sy1. Splitting of toluene-sulfonylglycyl-(D,L)-phenyl-alanine Splitting of N-p-t0luenesulfonyl-L(-)-tyrosine 3.14 grams of N-p-toluenesulfonyl-L-(-)-tyrosine are subjected to reductive cleavage as described above. Tyrosine, which is sparingly soluble in methanol, begins to precipitate in the course of the electrolysis. At the end of the electrolysis the product is rinsed with 2 N-sodium hydroxide solution in a separating funnel, mercury is separated OE and the clear solution is filtered. This is concentrated to a small volume and acidified by means of 2 N-hydrochloric acid in the cold. Para-toluene-sulfonamide which might not have reacted and the toluene-sulfinic acid are filtered off with suction and from the filtrate the free amino-acid is precipitated by means of sodium bicarbonate. Yield after drying: 1.7 g.=100%.

For purification, the amine is dissolved in 10 cc. of 2 N-hydrochloric acid and precipitated by means of sodium bicarbonate. Yield: 1.6 grams=95.7% of the theory. Determination of the specific rotation with c.=5.6 grams/ 10 cc. in a 1 dm. tube in 2 N-hydrochloric acid solution:

tu r-10.5

The splitting is carried out as described for N-p-toluenesulfonyl-tyrosine. 10 millimols of toluene-sulfonylglycyl- (D,L)-phenyl-a lanine yield 1.8 grams of glycyl-(D,L)- phenyl alanine, i.e. 81% of the theory. The substance is recrystallized in a mixture of alcohol and water (30:17).

Analysis.-Calculated for C H O NS (376.38): C, 59.44; H, 6.35. Found: C, 59.31; H, 6.26.

Splitting of N-benzoyl-glycylglycine The reductive splitting is effected as described for benzamides. From 2.8 grams of N-benzoyl-glycylglycine, 1 gram of pure glycylglycine is obtained (=75.6% of the theory).

We claim:

1. A process for reductively cleaving an aromatic carboxylic acid amide or an aromatic sulfonic acid amide into a corresponding amine and aromatic alcohol or aromatic sulfinic acid, respectively, which process comprises electrolyzing a solution of said amide in the presence of a tetraalkyl ammonium salt.

2. A process as in claim 1 wherein said tetraalkyl arn-a monium salt is tetramethyl ammonium chloride.

(References on following page) 5 References Cited FOREIGN PATENTS 6/1960 Russia.

OTHER REFERENCES Journal of the Electrochemical Society: preprint 84-8, Oct. 15, 1943, The Electrolytic Reduction of Amides, Sherlock Swan, Jr. pp. 67-73. 204-74.

JOHN H. MACK, Primary Examiner.

H. M. FLOURNOY, Assistant Examiner.

US. Cl. X.R. 20472