[CONTRIBUTION FROM THE
NOYESCHEMICAL LABORATORY, UNIVERSITY
OF ILLINOIS]
3-(p-DIMETHYLAMINOBENZAL)-6-NITROPHTHALIDE AKD 3-(p-DIMETHY LAMINOBENZYL)-6-AMIXOPHTHALIDE R. L. SHRINER
AND
LOUIS S. KEYSER
Received November 21, 1939
Although the methylene group in phthalide is not sufficiently reactive to condense with aldehydes, the introduction of a nitro group in the 6-position has been shown to cause the 6-nitrophthalide (I) to condense with aromatic aldehydes (1). I n the present work an attempt was made to carry out the Mannich reaction (2) on 6-nitrophthalide in order to obtain the 3-diethylaminomethyl-6-nitrophthalide(11). Reduction of the nitro
0
0
C
C
It
II
I
I1
group would then give a 6-amino derivative whose pharmacological properties would be very interesting. However, up to the present, it has not been possible to carry out the Mannich reaction on 6-nitrophthalide1 although a variety of experimental conditions were tried. Hence, attention was turned to the products obtainable by condensation with aryl aldehydes. 6-Nitrophthalide condensed smoothly with p-dimethylaminobenzaldehyde in the presence of piperidine to give an 87% yield of the benzal compound 111. This compound existed in three polymorphic forms. Crystallization from acetone or chloroform gave shining green hexagonal plates, while cooling of a saturated solution of the compound in benzene or dioxane yielded dark purple, almost black, plates. When the melting point of each of those forms was determined on the Kofler hot stage under a microscope, it was observed that as the melting point was approached, both changed over to a third form which consisted of reddish rhombic plates. This change was complete before melting occurred and only one melting point of the three forms was noted: uiz. 283-284'. The intense color of this compound is not surprising in view of its close 200
20 1
CONDENSATION O F 6-NITROPHTHALIDE
0
I
I11
v
0
I/
C
IV
VI
structural relationship to the phthaleins and the stilbene dyes (3). 4Kitrc)-4’-dimethylarninostilbene (IV), which contains a system of conjugat,ed double bonds and resonating groups identical with that in compound 111, is a red dye (4). Since the base (111) dissolved in ten per cent hydrochloric acid but precipitated on dilution, it was found possible to dye wool directly by treating the wool with a hydrochloric acid solution of the base and then washing thoroughly with water. The wool so treated was colored a bright autumn rust which was fast to washing and ultraviolet light. Catalytic reduction of the base (111) using Raney nickel and hydrogen a t a pressure of about 2000 pounds gave first the bright, irridescent, orange 3-(p-dimethylaminobenzal)-6-aminophthalide (V) and then, after filtering and addition of fresh catalyst, the canary yellow 3-(p-dimethylaniinobenzyl)-6-aminophthalide (VI). Both formed acetyl derivatives on treatment with acetic anhydride. The 3-(p-dimethylaminobenzyl)-6-aminophthalide (VI) is a vinylog ( 5 ) of the 6-amino compound derived from 11. Its salts with mineral acids were very hygroscopic. It failed to dissolve completely in one equivalent of dilute hydrochloric acid, but yielded a clear solution with two equivalents of acid. This solution proved to be so acidic that it was extremely irritating to the eyes and skin of a rabbit. Hence, no definite pharmacological studies of its action could be made. EXPERIMENTAL
6-h’itrophthalide. The method of Borsche, Diacont and Hanau (1) was used in the preparation of this compound. A mixture of 26.8 g. (0.2 mole) of phthalide in 30 cc. of concentrated sulfuric acid was added dropwise t o a mixture of 23 g. of
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R. L. SHRINER AND LOUIS S . KEYSER
potassium nitrate in 50 cc. of concentrated sulfuric acid cooled to 0". The temperature was not allowed to rise above 5" a t any time during the addition. After all of the phthalide solution had been added, the mixture stood twelve hours and was then decomposed on cracked ice. The crude product so obtained weighed 36 g. Recrystallization from dilute acetic acid yielded 28 g. (78% of the theoretical) of fine, pale yellow needles which melted sharply a t 145". J-(p-Dimethylaminobenzal)-6-nitrophthalide.Twelve grams (0.08 mole) of p-dimethylaminobenzaldehyde was heated a t 185-190" for one hour with 14.4 g. (0.08 mole) of 6-nitrophthalide and four drops of piperidine as catalyst. Water was evolved and the mixture became molten and turned dark purple. After cooling, the cake which formed was byoken up and ground in a mortar to a fine powder. I t was then extracted repeatedly with one liter of dioxane until none of the original powder was left. Concentration of the dioxane solution yielded very fine dark purple crystals amounting to 21.7 g. (87% of the theoretical). The product so prepared melted a t 283-284" with decomposition. Borsche, Diacont and Hanau (1) mention this compound in a footnote and give a melting point of 270" but no additional data. Anal. Calc'd for C I ~ H ~ ~ N C, ~65.80; O ~ :H I 4.55; N, 9.03. Found: C, 65.98; H, 4.66; N, 9.09. S-(p-Dimethylaminobenzal)-6-aminophthalide. A suspension of 6.2 g. (0.02 mole) of the beneal compound and 6 g. of Raney nickel in 700 cc. of purified dioxane was hydrogenated in a high pressure reducing machine (6) a t a pressure of 2100 pounds a t 90" for one hour. The catalyst was then filtered and the filtrate concentrated to 50 cc. Three grams (53.6% of the theoretical) of the bright orange crystals melting a t 259-262" separated. Anal. Calc'd for C1TH1&p02: C, 72.84; H I 5.76; X, 10.00. Found: C, 72.80; H, 5.99; K,10.25. The 3-(p-dimethylaminobenzal)-6-aminophthalidewas also prepared by catalytic reduction using platinum catalyst (7) in a 50% sulfuric acid solution under approximately three atmospheres pressure. S-(p-Dimethylaminobenzyl)-6-aminophthalide.A mixture of 7.3 g. (0.0235 mole) of the nitrobenzal compound dissolved in 1000 cc. of dioxane was hydrogenated for one hour a t a pressure of 2315 pounds, and a temperature of 100' using 6 g. of Raney nickel catalyst. The catalyst was filtered and fresh catalyst added to the highly fluorescent solution. 'The mixture was again hydrogenated for an hour a t a pressure of 2140 pounds and a temperature of 100". The catalyst was filtered and the dioxane distilled under reduced pressure until only about 50 cc. of liquid remained. The product separated in the form of bright yellow crystals which weighed 3.5 g. (53% of the theoretica1;l and melted a t 204.5'. Anal. Calc'd for C17H18NL02:C, 72.31; H, 6.43; K,9.94. Found: C, 72.30; H, 6.66; N, 10.05. This compound was likewise prepared by reduction in a 50% sulfuric acid solution using platinum catalyst. The aminobenxal compound was not isolated in this case but after the initial reduction of the nitro group, the catalyst was filtered and fresh catalyst added. The yields in these reductions in strong sulfuric acid were much lower, being on the order of 576. 5-(p-Dimethylaminobenzal)-6-acetylaminophthalide,This compound was prepared by boiling about a tenth of a gram of the aminobenxal compound for one hour with acetic anhydride. The excess acetic anhydride was decomposed by pouring the mixture into boiling water. The bright orange powder thus obtained
CONDENSATION O F
6-NITROPHTHALIDE
203
was recrystallized by evaporation of an alcohol solution of the compound which had been diluted with a small amount of water. The light fluffy plate-like crystals melted a t 287”. Anal. Calc’d for C I B H I ~ K Z O N,~ 8.6!). : Found: K, 8.44. 3-(,p-Dimethylaminobenzyl)-6-acetylaininophthalide.This was prepared by a procedurls similar to that followed in the preparation of the acetyl derivative of the aminobenzal compound. However, on decomposition of the excess acetic anhydride, the free base did not precipitate. Neutralization with dilute sodium hydroxide solution, however, yielded the yellow acetyl derivative. This powder was recrystallized from a water-alcohol mixture prepared by adding water dropwise to a hot alcohol solution of the compound until a slight cloudiness, which was then destroyed by addition of a drop of alcohol, was produced. The granular yellow crystals melted a t 210’. Anal. Calc’d for CloHzoNzOs: N, 8.64. Found: N, 8.69. SUMMARY
6-Nitrophthalide did not undergo condensation in the Mannich reaction, but did condense with p-dimethylaminobenzaldehyde to produce 3-(pdime thylaminobenzal)-6-nitrophthalide. This compound was highly colored and was found to be a direct dye for wool. Catalytic reduction of 3-(p-dimethylaminobenzal)-6-nitrophthalideproduced first the substituted 6-aminophthalide, and complete reduction formed 3- (p-dimethylaminobenzyl) -6-aminoph t halide. URBANA,ILL. REFERENCES (1) BORSCHE,DIACONTAND HANAU,Ber., 67, 675 (1934). (2) MANNICH,Arch. Pharm., 266, 261 (1917); MANNICH AND BRAUN,Ber., 63, 1874 (1920). (3) THORPE AND LINSTEAD,“The Synthetic Dyestuffs and Intermediate Products from Which They Are Derived,” Charles Griffen and Co., Ltd., London, pp. 113, 163 (1933). (4) PFEIFFER, Ber., 48, 1782 (1915). (5) FUSON, Chem. Rev., 16, 1 (1935). (6) ADKINS, “Reactions of Hydrogen with Organic Compounds over CopperChromium Oxide and Nickel Catalysts” University of Wisconsin Press, Madison, Wis. (1937). (7) 0,rganic Syntheses Coll. Vol. I, John Wiley and Sons, New York, p. 452 (1932).
