[CONTRIBUTION FROM
RESEARCH LABOBATORIES, SCHOOL UNIVERSITY OF MARYLAND]
TEE
OF
PHARMACY,
SYNTHEHS OF SOME STILBAZOLE DERIVATIVES MING-CHIEN CHIANG'
AND
WALTER H. HARTUNG
Received August 19, 1944
Browning and co-workers (1,2,3)have shown that stilbazoles (styrylpyridines) and styrylquinolines possess marked antiseptic and trypanocidal activity. They synthesized a number of the quinoline compounds, such as styryl 430, and one of the pyridine derivative, 2-p-dimethylaminostyrylpyridinemethiodide. The styrylquinolines were found to be very powerful antiseptics and the substitution of a simple pyridine nucleus for a quinoline caused a slight reduction of the antiseptic power. Structurally, stilbazoles (I) are analogous to anil pyridine compounds (11) and the azo dyes of pyridine such as Pyridium (111). The anil pyridine compounds show marked antiseptic properties (2) and Pyridium is a genito-urinary antiseptic. It seems likely that the stilbazole skeleton might have some antiseptic properties.
I
I1
I11
The introduction of a hydroxyl group into the benzene nucleus of a stilbazole molecule converts it into a hydroxystilbazole, and the hydrogenation of the vinylene double bond gives a dihydrostilbazole. Thus the hydroxystilbazoles and the hydroxydihydrostilbazoles may be looked upon as pyridinoethylene- and pyridinoethyl-phenols, respectively. Since alkylated phenols and their derivatives are used extensively as antiseptics and bactericides, these modifications might provide possibilities for augmentation of the antiseptic activity. The higher alkylpyridinium salts such as the quaternary cetylpyridinium salt are excellent germicides (4). The combination of a stilbazole skeleton, a phenolic hydroxyl group and a quaternary pyridinium salt, all of which are individually more or less active as antiseptics, ought to prove interesting. The methods for the synthesis of a- and ystilbazole skeletons are all based on the condensation of a- and y-picolines, respectively, with benzaldehyde derivatives. The methyl group in P-picoline was found unreactive toward aldehydes and no such condensation has been observed ( 5 ) . The simple P-stilbazole has been synthesized from j3-pyridyl methyl ketone and a Grignard reagent (6). The condensation of the picolines with aldehydes to form stilbazoles is reported to proceed in two stages (7). The first is the formation of the stilbazole alkines, 1 Present address : The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
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CHIANG AND HARTUNG
and the reaction is reversible. The second is the dehydration of the alkines to stilbazoles:
OH In any case, the dehydration proceeds rapidly compared with the rate of the formation the stilbazoles, so that the first step (a) is the factor which determines the rate. Usually the condensation is very slow and requires prolonged heating from ten to thirty-six hours (7). The condensation agent widely used in early days was zinc chloride, with or without additional agents such as hydrochloric acid (8-13). The yields were usually poor, especially with hydroxybenzaldehyde derivatives (8, 10). Piperidine was also used by a number of investigators (3, 14). Recently, acetic anhydride has been most generally used and found to give higher yields and purer products (7, 13). Condensation by heating the reactants without condensing agent was also reported by some authors (7, 15, 16). In the present work, the zinc chloride method was tried. Zinc chloride alone gave very poor yields. With zinc chloride and hydrochloric acid, the results were better. The method using concentrated hydrochloric acid alone, which seems not to have been used before, gave still better results. However, the yield in no case exceeded 60%. The yield from condensation by heating without condensing agent was also very poor. By the acetic anhydride method, using an excess of the condensing agent, the yield was increased to about 72%. For the hydrogenation of stilbazoles to dihydrostilbazoles, the use of hydriodic acid, hydriodic acid and red phosphorus, and catalytic hydrogenation are reported (9, 17). Palladium catalyst prepared according to Hartung (18) was found very satisfactory in this work. Although the quaternary pyridinium salts of stilbazoles could be synthesized either by condensation of picolinium alkyl halides with a benzaldehyde derivative (3,14), or by heating the stilbazole with an alkyl halide (19), it seemed better to use the latter method and isolate the stilbazole first. The antiseptic properties of the compounds prepared have not been completely explored, but preliminary tests do not show great activity. The quaternary salts were disappointing; perhaps the aliphatic alkyl group should be larger, as it is in Zephirol. EXPERIMEh-TAL
Condensation of picolines with aldehydes. A mixture of the picoline (93 g., 1.0 mole), the desired aromatic aldehyde (from 0.85 t o 1.5 moles), and the condensing agent (30-50 ml. of concentrated hydrochloric acid or 1.0mole of acetic anhydride) was refluxed on an oil-bath for six t o twelve hours. The unchanged picoline was distilled off a t the same temperature. If an excess of the aldehyde was used, it was removed by steam distillation. The residual liquid was cooled and poured slowly into 150-200 ml. of cold water with stirring. The precipitate or solid mass formed was washed with several portions of water. In case an
SYNTHESIS OF STIIJBAZOLE DERIVATIVES
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CHIANG AND HARTUNG
oily mass was formed, it was washed with several small portions of dilute sodium hydroxide solution and finally with water. Usually the oil solidified into a mass upon cooling in an ice-box overnight. The product was filtered, washed with water, and dried in air. Purification was effected by repeated recrystallizations from ethanol. An excess of a mixture of B,r-picolines obtained from Reilly T a r and Chemical Corp. was used for the 7-compounds, and the yields were calculated on the basis of the aldehyde used. Hudrogenation of stilbazoles to dihydrostzlbazoles. In 100 ml. of ethanol, 20 g. of the stilbazole was dissolved and hydrogenated with a palladium catalyst prepared from 0.3 g. of palladium chloride according t o Hartung (18). Absorption of one mole of hydrogen for one mole of the stilbazole occurred, after which the hydrogenation was very slow and was stopped. The catalyst was filtered off and most of the solvent was removed by distillation under reduced pressure on a water-bath. An oily residue was left which solidified upon cooling in an ice-bath. Purification was effected by repeated recrystallizations from ethanol, benzene, or ligroin. Preparation of the stilbazole alkyl halides. A mixture of the stilbazole (0.05 mole) and an equivalent amount of alkyl halide in ethanol (20 ml.) was heated on a water-bath for four to six hours. Most of the ethanol was removed by distillation under reduced pressure. The crystalline product formed upon cooling was collected on a suction filter, washed with a little ethanol-ether mixture and dried. Repeated recrystallizations from ethanol, benzene, and ethanol-benzene mixture gave the pure product. The compounds prepared are listed in Tabla I. SUMMARY
Some stilbazoles, hydroxystilbazoles, dihydrostilbazoles, and hydroxydihydxostilbazoles of the a- and y-series have been synthesized by condensation ofaand y-picolines with aromatic aldehydes, followed by catalytic hydrogenation to the dihydro derivatives. Their quaternary pyridinium salts have been prepared by heating the stilbazoles with alkyl halides. The following new compounds have been synthesized : o-hydroxy-a-dihydrostilbazole, p-hydroxy-astilbazole and its ethiodide, p-hydroxy-a-dihydrostilbazole and its ethiodide, a-stilbazole n-hexiodide, y-stilbazole ethiodide, y-dihydrostilbazole ethiodide, and o-hydroxy-a-stilbazole ethiodide. BALTIMORE, MD. REFERENCES
(1) ASHLEY,BROWNING, COHEN,AND GULBRANSON, Proc. Roy. SOC.,B 113, 293 (1933). ELLINGSWORTH, AND GULBRANSON, J. Path. Bact., 27,121 (1924). (2) BROWNING, (3) BROWNING,COEEN, ELLINGSWORTH, AND GULBRUSON,Brit. Med. J., 1923, 11, 326 (1923). (4) WARREN, BECKER,MARSE,AND SHELTON, J . Pharmacol., 74, 401 (1942). (5) SIDGEWICK, “The Organic Chemistry of Nitrogen,” New edition, revised and rewritten by Taylor and Baker, Oxford Clarendon Press, London, 1937, p. 534. (6) HURDAND WEBB,J. Am. Chem. SOC.,49, 546 (1927). (7) SHAWAND WAGSTAFF,J. Chem. SOC.,77, (1933). (8) BAILEYAND MCELVAIN,J . Am. Chem. SOC., 62,1633 (1930). (9) BAURATR,Ber., 20, 2719 (1887);21, 818 (1888). (10)BRAMSCH,Ber., 42, 1193 (1909).
SYNTHESIS OF STILBAZOLE DERIVATIVES
(11) FRIEDLANDER, Ber., 38, 159 (1905). AND SMIRNOV, Khim. Farm. Prom., 1934, No. 4, 15. (12) OPARINA (13) WAQSTAFF, J. Chem. SOC.,276 (1934). (14) MILLSAND POPE,J . Chem. Soc., 121, 946 (1922). (15) FEIST,Ber., 34, 464 (1901). (16) RATHAND LEHMANN, Ber., 68, 342 (1925:i. Ber., 38, 2837 (1905). (17) FRIEDLANDER, J. Am. Chem. SOC.,M), 3370 (1928). (18) HARTUNG, (19) BUTTER,Ber., 23, 2697 (1890). (20)FELN,Ber., 37, 2147 (1904).
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