ROBERT F. COLESAND CLIFFS.HAMILTON
2588
VOl. 68
[cOSTRIBUTIOY FROM AVERYTdAr30RATORY OF CHEMISTRY O F TIIE UNIVERSLTY OF r\'EnRASKa] Arsenicals of the 5-Pyrazolone, 5-Isoxazolone and a-Acetoglyoxylic Acid Series BY ROBERT F. COLESAND CLIFFS. HAMILTON
Experimental During the course of a recent investigation by the authors' and in conjunction with the work of Ethyl ~~-Acetoglyoxylate Arsonophenylhydrazone (GenSharp and Hamilton,2 i t was decided to examine eral Procedure) .-The appropriate arninobci~ze~iearsonic several a-acetoglyoxylate arsonophenylhydra- acid (0.115 mole) was dissolved in a solution of sodium zones, 4-(arsonophenylazo)-3-methyl-5-pyrazol-hydroxide (5 g., 0.125 mole) and sodium nitrite (8.1 g., 0.115 mole) in 100 ml. of water. The resulting solution ones :md 4-(arsonophenylazo)-3-methyl-5-isox- was poured slowly with stirring into a solution of rcagent azolones as potential therapeutic agents. grade hydrochloric acid (50 nil., 0.625 niolr) i n 300 g. of The procedure of Sharp and Hamilton2 for the ice and water. The solution of the diazonium salt was poured with stircoupling of p-aminobenzenearsonic acid and into a solution consisting of sodiuni accxtate 155 g., ethyl acetoacetate was employed t o condense o- ring 0.025 mole), ethyl acetoacetate (15 g., 0.125 iliole), 95% and m-aminobenzenearsonic acids and %nitro- cthanol (50 nil.) and ice and water (800 g.). 111e mixturc 4-aminobenz(~1earsonicacid with ethyl acetoace- was cooled in a refrigerator overtlight and acidified to congo red paper in the cold with hydrochloric a c s i d . The tate. I product was crystallized ~ ~ O I I aqueous Chattaway and Ashworth3reported that aceto- precipitated cthanol. acetic acid evolves carbon dioxide when coupled adcetoglyoxylic Acid 4-Arsonophenylhydrazone (11) .with +nitrobenzene diazonium chloride to yield A solution of I (8 g., 0.022 mole) in 300 ml. of a saturated pyruvaldehytle p-nitrophenylhydrazone. It was solution of barium hydroxide was refluxed for tbvo hours. The yellow precipitate was collected 011 a filter and expected, therefore, that ethyl a-acetoglyoxylate washed well with water. A suspension of the solid in p-arsonophenylhydrazone (I) when subjected to water was made strongly acid with hydrochloric acid; the the acetoacetic ketonic hydrolysis with dilute resulting tan solid was collected and washed with water, base should yield the corresponding pyruvalde- ethanol, and ether successively. The product was purified reprecipitating from bicarbonate solution rvith hydrohyde p-arsonophenylhydrazone. However, hy- by chloric acid, yield 6 g. drolysis with saturated barium hydroxide solu4- (4-Arsonophenylazo) -3-methyl-5-pyrazolone (111).tion produced an insoluble barium salt which when A solution of I (5 g., 0.014 mole), in 75 ml. of watct-, conconverted to the free acid gave an analysis for CY- taining sodium hydroxide (3 g., 0.075 mole), wab treated with a solution of hydrazine dihydrochloride ( 3 g., 0.028 acetoglyoxyli: acid-p-arsonophenylhydrazone(11). mole) in 50 ml. of water. The solution was warmed on a Apparently a normal ester hydrolysis without steam-bath for two hours and allowed to stand overnight. decarboxylation occurred. The reaction niisturc vas acidified to congo red paper TABLE I ARSENICALS Compound
Crystn. solvent
Yield,
%
Mi$'
Formula
.4n.~lyies, A i c Calctl. 1:ound
Ethyl cu-acetoglyoxylateo-Arsonophen ylhydrazone 30y0 Ethanol 90 182.5-153.5 CIZHISASNZOG 20.92 21.09 m-Arsonophenylhydrazone 50% Ethanol 92 197-198 C1zHi&SN?O~ 20.92 21.1 1 4-Arsono-2-nitrophenylhydrazone Aq. ethanol 81 251-252 dec. C1zHl4AsN3O8 18.58 18.3i Acid a-acei.oglyoxylic4-Arsonophenylhydrazone (11) 82 240-2.11 der. CIOI-IIIAsN:OG 22.69 2 2 . ii7 3-Methyl-5-pyrazolone4- (2-Arsonoplienylazo) Aq. ethanol 22 268-269 dec. CIOHIIAsN4O4 22.07 22.90 b 4-(3-Arsonophenylazo) 65>250 C I O H I I A S K ~ O ~22.97 22.91 b CioIIiiAsN~O~ 22.97 22.70 4- (4-Arsonophenylazo) (TII) 44 >250 4- (Z-Nitro-4-:irsonophenylazo) b 32 >250 CiuHioAsN:,Oe 2 0 , 18 19.99 3 Mctliyl-5-isoxazolone4- (2-Arsonophenylazo) Aq. ethanol 28 232-233 CioFIioAsN~0s 22,E)O 22.67 4- (3-Arsonoplicnylazo) (IV) Aq. ethanol 55 >250 C i o H i & S ~ O ~ 22.90 22,8fi a Purified by reprecipitation from sodium bicarbonate solution by the addition of hydrochloric acid. f'urificd by reprecipitation from barium hydroxide solution by the addition of hydrochloric acid. Method of Cislak and Hamilton, THISJOURNAL, 52, 638 (1930).
The arsonophenylhydrazones of ethyl a-aceto- with hydrochloric acid. The precipitated solid was coldissolved in hot dilute barium hydroxide solution glyoxylate when treated with hydrazine or hy- lected, and filtered. The filtrate was acidified with hydrochloric droxylamine in basic solution yielded the cor- acid, the product collected, washed with water, ethanol responding 4-(arsonophenylazo)-3-methyl-5-pyra- and ether; yield 2 g. The preparation of other pyrazolones was accomplished zolones or 5-iaoxazolones. by analogous procedures. (1) Coles a n d Hamilton, THISJOURNAL, 68, 1799 (1946). (2) Sharp and Hamilton, tbid , 6 8 , 588 (1946).
(3) Chottaway :ind Asbworth, J . Chcm. Soc , 475 (1933).
4-(3-Arsonophenylazo) -3-methyl-5-isoxazolone (IV) .-
A solution of ethyl a-acetoglyoxylate 3-arsonophenylhydrazone (5 g., 0.014 mole) in 75 ml. of water, containing
Dec., 1916
METHYLENE AND ~ P H B N Y L EAN.ILOGS NE OF PLASMOCID
sodium bicarbonate (2.36 g., 0.028 mole), was treated with hydroxylamine hydrochloride (1.5 g., 0.022 mole) in 25 ml. of water. The prrcipitated solid was redissolved by the addition of solid sodium bicarbonate arid thc solution warmed for two hours. Ai1 additional 2 g. of sodiuiii bicarbonate was added and the heating continued for two more hours. The reaction mixture was acidified to congo red paper with hydrochloric acid, filtered, and the solid washed with watrr, ethanol, and ether. Crystallization was effected from aqueous ethanol; yield 2.5 g. Othcr isoxazc)lonrs were prepared by similar procedures.
Summary 1. Several nminobfrizerienrsonic acids have
2389
been diazotized and coupled with ethyl acetoacetate. 3. The products from (I) have been treated with hydr,izine or hydroxylanline in the presence of base to qive. the corresponding 4-(arsonnphcnylazo)-~~-mcthyl-,5-pyrazolones or 5-isoxazolones. 3. The barium hydroxide hydrolysis of cthyl a-acetoglyoxylate-4-arsonophenylhydralone produced normal ester hydrolysis rather than the expected acetoacetic ketonic hydrolysis. RECEIVED SEPI EMBER 6, 1946 L I U C O I . SEDRASKA ~,
[ CONTRIRUTIOX FROM SOYES CHEMICAL LABORATORY, UXIVERSITY 01;ILLIxoIs1
Methylene and p-Phenylene Analogs of Plasmocid' BY CHARLES C. PRICE,* H. R. SNYDER AND EARLEM. VAN HEYNINGEN I n order to evaluate the effect of interposing a methylene or phenylene residue between the amino side chain and the nucleus in the S-aminoquinoline series, two analogs of 6-methoxy-8-(diethylaminopropylamino)-quinoline, sometimes referred to as Ptasmocid, have been prepared. The synthesis of both compounds started from 6-methoxy-8-aminoquinoline. The methylene analog was prepared by replacement of the amino group with cyano, preferably through the chloro compound by treatment with cuprous cyanide. The 8-cyano compound was reduced catalytically and thtv treated with 3-dieth~lamiiiopropylchloride.
was diazotized and the product coupled directly with nitrobenzene. ( 3 ) The amino group was acetylated, nitrosated and coupled with nitrobenzene. ( 3 ) The salt of diazotized I with 1,S-naphthalenedisulfonic acid was isolated and coupled with nitrobenzene. The last was the most convenient procedure.
Experimental4 8-Cyano-6-methoxyquinolineby the Sandmeyer Reac3 g. . (0.017 mole) of 8-amino-6-methoxytion.-To
quinoline was added a solution of 1.1 ml. (0.02 mole) of concentrated sulfuric acid (sp. gr. 1.84) in 50 ml. of water. The mixture was heated t o dissolve the yellow sulfate that formed, and then cooled rapidly a n in ice-bath t o reprecipitate the sulfate in fine needles. The HOXO, C u C S (10%) cooled susDension was diluted with a solution of'3.3 ml. (0.06 mole) of sulfuric acid in 50 ml. of water and then C H a o ) ~ p ~ HOSO c11C: diazotized a t a temperature below 5" + Iwith a 5 N sodium nitrite solution to a CUCl starch-iodide end-point. A deep red solid formed during the course of the 1 I diazotization and this was filtered from NHz c1 CK the diazotization mixture. The filtrate I M. p. 60' (827,) M. p. 1510 (43%',) was made neutral to red litmus paper with cold 3001, sodium hydroxide by H zXi~ gradual addition such that the temCH perature of the mixture did not rise above 5'. A pink precipitate formed. This neutral suspension was poured \/ s' slowlv with stirring into 23 ml. of 1 A' sodium cuprous cyanide cooled in an CFT? CH? ice-bath. No visible change occurred so the mixture was stirred overnight, I I SH(CH?)3Ii(C?HQ)1 "2 thus slowly coming to room tempera(319) M , p. 870 ( ~ 7 % , ) ture. Then the solid in the mixture was collected and extracted with 50 ml. SK-l4,7i33 of boiling 95% ethanol. The alcohol The p-phenylene analog was prepared by three extract was evaporated to dryness on a steam-bath and the dark residue dissolved by heating in a minimum amount similar procedures: (1) The amino group of I of 20% acetic acid. The hot acetic acid solution was treated with a small amount of Darco and filtered. The (1) The work reported was carried o u t under a contract recomwhite crystals that formed on cooling were 8-cyano-6mended by t h e Committee on Medical Research. between the Office rnethoxyquinoline, m. p. 147-150" (9.5%,). of Scientific Research a n d Development and t h e University of Replacing the sulfuric acid by phosphoric or hydrochloric Illinois. acid did not change the yield. Addition of the acidic ( 2 ) Present address: University of Notre Dame, Notre Dame, diazonium solution t o a solution of sodium cuprous cyanide Indiana. and excess sodium cyanide a t either 50 or 100' gave none (3) T h e Survey Number, designated SN-, refers t o the number asof the desired 8-cyano-6-methoxyquinoline. signed by t h e Susvey of Antimalarial Drugs. T h e activity of such
/-
c1T30'pA C H 3 0 y A
k!\-.r
cH30' 0c r
compounds will bt. compiled in a forthcoming monograph.
(4) Analyses were performed by Misses T. Spoor and I,. Hruda.
