LABORATORY, UNIVEREITY OF VIRGINIA]
[~ONTBIBUTIONFROM T E E COBB CHEMICAL
SOME DERIVATIVES O F HOMOANISIC ACID ALFRED BURGER
AND
S. AVAKIAN
Received June 96, 1940
In the course of synthetic experiments in the dibenzothiophene series, a number of phenylacetic acid derivatives containing thio and thio ether groups were needed. Their preparation is described in this article. p-Homoanisic acid (4-methoxyphenylacetic acid) which served as our starting material, may be obtained in several ways (1). We found it advantageous to prepare it by the Arndt and Eistert synthesis (2) from p-methoxybenzoyl chloride through p-methoxyphenyl diazomethyl ketone and p-homoanisamide. The over-all yield of homoanisic acid, based on p-methoxybenzoic acid, was 53%. Nuclear bromination (3) of p-homoanisic acid directs the bromine atom into position 3. We found that nitration and chlorosulfonation also direct the incoming substituent into the 3-position. This was proved by reducing nitrohomoanisic acid to aminohomoanisic acid, and converting this product to homoisovanillic acid (4). The reaction between homoanisic acid-3-diazonium chloride and a sodium sulfide solution (5) furnished 3,3'-dithiohomoanisic acid, which was reduced to 3-thiohomoanisic acid. This product was also obtained by reduction of 3-chlorosulfonyl homoanisic acid with zinc dust and acids (6). A further proof of the structure of this series of compounds consisted of the alternate synthesis of 3-nitrohomoanisic acid from 3-nitro-4-methoxybenzyl cyanide, which was prepared from the known 3-nitro-4-methoxybenzyl chloride (7). Condensation of 3-thiohomoanisic acid with 2-nitro-3-bromobenzoic acid led to 2'-nitro-3'-carboxy-2-methoxydiphenyl sulfide-&acetic acid which was reduced to the corresponding amino derivative by ferrous hydroxide in ammonium hydroxide suspension. EXPERIMENTAL
p-Methoxyphenyl diazomethyl ketone. One hundred and fifty grams of p-methoxybenzoyl chloride was added to an ethereal solution of diazomethane obtained from 380 g. of nitrosomethylurea, and the solution was allowed to stand overnight. The solvent was distilled off, and the crystalline reaction-product was recrystallized from benzene. The diazo ketone appeared as transparent hexagonal prisms, m.p. 90-91". The yield was 109 g. (70.3%). Anal. Calc'd for C P H S N ~ ON, ~ :15.82. Found: N, 15.98. 606
DERNATIVES OF HOMOANISIC ACID
607
p-Homoanisic acid. A solution of 20 g. of the diazo ketone in 100 cc. of dioxane was treated with 150 cc. of concentrated ammonium hydroxide and 30 cc. of 10% silver nitrate solution a t 60-70". The mixture was boiled under reflux for two hours, cooled, and p-homoanisamide (8) was precipitated by addition of water. Recrystallization from alcohol yielded 15 g. (8lY0) of the pure amide, m.p. 188-189". A solution of 20 g. of p-homoanisamide and 40 g. of potassium hydroxide in 400 cc. of alcohol was boiled on a steam-bath under reflux for five hours. The solution waa diluted with 1 liter of hot water, concentrated t o 100 cc., and acidified. The homoanisic acid was filtered, washed, and dried. It melted a t 86-87". The yield was 17 g. (85%). 3-Chlorosulfonyl homoanisic acid. Sixteen and six-tenths grams of homoanisic acid was added to 30 cc. of chlorosulfonic acid a t -5" a t such a rate that the temperature did not rise above 0". The mixture was kept below 0' for one hour, the temperature was then allowed to rise to No,and kept a t this point for five minutes. It was then cooled, poured onto ice, the crude sulfonyl chloride was filtered, and recrystallized from benzene. It appeared as colorless prisms, m.p. 164-165". The yield was 21.3 g. (80.6%). Anal. Calc'd for CoHoClObS: Cl, 13.44; CHsO, 11.76. C1, 13.58; CHsO, 11.61. Found : 3-Thio-p-homoanisic acid. Twelve grams of zinc dust was added to a mixture of 72 g. of ice and 24 g. of concent>ratedsulfuric acid a t -5". Nine grams of 3-chlorosulfonyl homoanisic acid was added with mechanical stirring, and the temperature was raised slowly to 80" in the course of two hours. At the end of this time the mixture was cooled, diluted with water, and the precipitate filtered. The thiohomoanisic acid waB dissolved by boiling the precipitate in a 15%sodium hydroxide solution for five minutes, filtered from insoluble material, and reprecipitated by acidifying the filtrate with hydrochloric acid. The crude compound melted a t 79-82" and weighed 6.1 g. Recrystallization from benzene-petroleum ether gave colorless prisms, m.p. 83-84". The yield wm 5.6 g. (83%). C, 54.49; H, 5.09. Anal. Calc'd for COHWO~S: C, 54.62; H, 5.23. Found : The compound proved to be identical with 3-thiohomoanisic acid prepared from 3-aminohomoanisic acid (see below). 3-Nitro-4-methoxybenzyl cyanide. A solution of 30 g. of 3-nitro-4-methoxybenzyl chloride (7), 10 g. of potassium cyanide, and a few crystals of potassium bromide in 300 cc. of alcohol was boiled under reflux on a steam-bath for six hours, and then evaporated almost t o dryness under reduced pressure. Addition of 500 cc. of water furnished yellowish rhombic prisms which, after recrystallization from alcohol, melted at 87-87.5". The yield was 15.5 g. (54%). Anal. Calc'd for COHJTIOI: N, 14.58. Found: N, 14.63. 3-Nitro-p-homoanisic acid. (a) A solution of 3 g. of 3-nitro-4-methoxybenzyl cyanide in a mixture of 5 cc. of 50% sulfuric acid and 5 cc. of glacial acetic acid was boiled under reflux for two hours, cooled, and diluted with water. The crude precipitate was filtered, and recrystallized from alcohol. 3-Nitrohomoanisic acid appeared as colorless plates, m.p. 132-133'. The yield was 2.3 g. (70%). Anal. Calc'd for C&ONOI: N, 6.60. Found: N, 6.81. (b) A solution of 0.5 g. of homoanisic acid in 5 cc. of glacial acetic acid was cooled and treated with 1 cc. of concentrated nitric acid while the temperature was kept below 0". After ten minutes, the solution was diluted with water, the precipitate was filtered, and recrystallized from alcohol. The crystals melted a t 132-133",
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BURGEF&.NDTAVAKIAN
the yield was 0.3 g. A mixture melting point with 3-nitro-p-homoanisic acid prepared by hydrolysis of the nitrile showed no depression. 8-Aminohomoanisic acid. Sixteen grams of 3-nitrohomoanisic acid, dissolved in 200 cc. of alcohol, was hydrogenated in the presence of 0.5 g. of Raney nickel catalyst. The catalyst was filtered, the solvent evaporated, and the solid residue recrystallized from benzene. The amino acid appeared as colorless needles, m.p. 110-11lo. The yield was 12.3 g. (90%). Anal. Calc'd for CpHllNOs: C , 59.64; H, 6.12. Found : C, 59.65; H, 6.08. Homoisooanillic acid (4). Two and seven-tenths grams of 3-aminohomoanisic acid was dissolved in a cold mixture of 5 cc. of water and 3.5 cc. of concentrated sulfuric acid with stirring. Eight grams of ice was added, and a solution of 1 g. of sodium nitrite in 2 cc. of water was dropped in slowly a t 0" over a period of five minutes. The solution was allowed to stand for one hour and then dropped into 15 cc. of boiling 40% sulfuric acid. A dark solid precipitated on cooling. Extraction of the precipitate with boiling ethyl acetate, and precipitation with low-boiling petroleum ether furnished light-colored crystals of homoisovanillic acid. Another small amount of this material was obtained by sublimation in a high vacuum of the undissolved residue from the ethyl acetate extraction. Recrystallization from benzene-petroleum ether yielded colorless crystals, m.p. 127-128". 3-Thiohomoanisic acid from 8-aminohomoanisic acid. A cold solution of 2.7 g. of sodium nitrite in 12 cc. of water waa added slowly to a mixture of 7.24 g. of 3-aminohomoanisic acid, 20 cc. of water, and 8 cc. of concentrated hydrochloric acid at -5". After ten minutes, the diazo solution was added carefully at -5" to an alkaline sodium sulfide solution prepared by dissolving 12.4 g. of sodium sulfide (NazS.9HtO) and 1.3 g. of powdered sulfur in 12 cc. of boiling water, and treating the mixture with a solution of 1.6 g. of sodium hydroxide in 4 cc. of water. Nitrogen was evolved, and the solution was allowed to stand at room temperature for one hour. Acidification with acetic acid caused precipitation of 3,3'-dithiohomoanisic acid. Excess sulfur was removed by dissolving the precipitate in hot sodium carbonate solution, filtering, and reprecipitating the disulfide with hydrochloric acid. The acid solution was decanted, and the semi-solid disulfide was washed with several portions of water. Two grams of zinc dust and 20 cc. of glacial acetic acid were added, and the mixture was boiled under reflux for one hour. The solution was concentrated, and then diluted with 100 cc. of water. The precipitate was filtered, boiled with 20 cc. of 15% sodium hydroxide solution for ten minutes, the solution was filtered, and the thiohomoanisic acid was precipitated from the filtrate by acidification. Sublimation at 0.1 mm. pressure, and recrystallization from benzene-petroleum ether gave colorless crystals, m.p. 83-84". The yield was 25%. A mixture melting point with 3-thiohomoanisic acid prepared by reduction of 3-chlorosulfonyl homoanisic acid showed no depression. 2-NitroJ-bromobenzoic acid. The oxidation of 2-nitro-3-bromotoluene was carried out with chromic acid (9) in place of a neutral potassium permanganate solution as described by Elson, Gibson, and Johnson (10). Sixty-five grams of concentrated sulfuric acid was added with mechanical stirring t o a mixture of 26 g. of sodium dichromate, 60 cc. of water, and 14 g. of 2-nitro-3bromotoluene. The mixture was boiled under reflux for twenty minutes, cooled, and diluted with water. The precipitate was filtered through cloth, washed with water, agitated with 30 cc. of 5% sulfuric acid, and filtered again. It was extracted with boiling 15% sodium hydroxide solution for ten minutes, and the 2-nitro-3bromobeneoic acid was precipitated from the filtered alkaline solution by acidifica-
DERIVATIVES OF HOMOANISIC ACID
609
tion with dilute sulfuric acid. Recrystallization from dilute alcohol furnished 11 g. (70%) of the pure acid, m.p. 250-251'. A mixture melting point with an authentical sample prepared by the method of Friedlander, Bruckner, and Deutsch (11) showed no depression. B'-Nitro-3'-carbozy-k?-methoxydiphenyl sulfide-6-acetic acid. A mixture of 1.24 g. of 3-thiohomoanisic acid and 2.46 g. of 2-nitro-3-bromobenzoic acid was dissolved in a solution of 1.23 g. of potassium hydroxide in 5.6 cc. of methanol. The solvent was evaporated, the mixture was heated slowly to 190",and kept a t this temperature for two hours. The dark brown solid was dissolved in cold water, the solution was extracted with ether, and acidified. The gray crystalline precipitate was filtered, dried, and boiled out with benzene. The insoluble portion was recrystallized from dilute alcohol. The diphenyl sulfide derivative appeared as small yellowish cubes, m.p. 232-234" (decomp.). The yield was 1.0 g. (46%). Anal. Calc'd for ClSHlsNOrS: C, 52.87; H, 3.61. C, 52.93; H, 3.84. Found: B'-Amino-9'-carboxy-B-methoxydiphenyl sulfide-6-acetic acid. A solution of 0.35 g. of the nitro derivative in 10 cc. of hot concentrated ammonium hydroxide was added slowly to a suspension of ferrous hydroxide (from 1.52 g. of ferrous sulfate) in 13 cc. of hot dilute ammonium hydroxide. The mixture was stirred on a steam-bath for thirty minutes, and the ferric hydroxide was filtered and washed with several portions of hot dilute ammonium hydroxide. The filtrate was concentrated under reduced pressure to about 50 cc., then acidified with acetic acid, and the yellowish amino acid was filtered. Recrystallization from alcohol furnished 0.22 g. (66%) of colorless diamond-shaped crystals, m.p. 222-224". Anal. Calc'd for ClsHk~NOsS:C, 57.63; H, 4.54; N, 4.20. C, 57.73; H, 4.71; N, 4.45. Found : SUMMARY
The synthesis of 3-thiohomoanisic acid and two substituted carboxy diphenyl sulfide acetic acid derivatives is described. UNXVIDBSITY, VA. REFERENCES (1) PSCHORR, WOLFES,AND BUCKOW, Ber., 33, 162 (1900);KONDOAND OSHIMA,J . Pharm. SOC.Japan, 61, 979 (1931); KINDLERAND PESCHKE,Arch. Pharm., 271, 431 (1933). Cj. SCHOPF AND WINTERHALDER, Ann., 544, 62 (1940). (2) ARNDTAND EISTERT,Ber., 66,200 (1935). AND UYEO,J . Pharm. Soc. Japan, 63,557 (1933). (3) KONDO (4) SPATHAND LANG,Monatsh., 41, 273 (1921); HAHNAND SCHULZ,Ber., 72, 1302 (1939). (5) Cj. ALLENAND MACKAY,Org. Syntheses, 12,76 (1932). (6) Cj. ADAMSAND MARVEL,Org. Syntheses, Coll. Vol. I, 490. (7) QUELETAND GERMAIN, Compt. rend., 202, 1442 (1936). Ber., 22,2137 (1889). (8) SALKOWSKI, Org. Syntheses, Coll. Vol. I, 385. (9) Ci. KAMMAND MATTHEWS, (IO) ELSON,GIBSON,AND JOHNSON, J . Chem. SOC.,1929, 2741. (11) FRIEDL~NDER, BRUCKNER, AND DEUTSCH, Ann., 388, 23 (1912).
