[CONTRIBUTION FROM
PURDUB RESEARCH FOUNDATION AND THE DEPARTMENT CHEMISTRY, PURDUE UNIVERSITY]
THE OF
COMPOUNDS OF PHARMACEUTICAL INTEREST FROM 4-METHOXY1-NAPHTHYLAMINE G. BRYANT BACHPVZAN
AND
JOHN W. WETZELI
Receiaed January 88, 1946
From 4-methoxy-1-naphthylamineand its tetrahydride, 4-methoxyd ,6,7,8tetrahydro-1-naphthylamine, have been prepared substituted benz(clacridines and benzo(h)quinolines similar to compounds of kn0u.n antim.alaria1 activity. Benz(c)acridines. The above amines were condensed with 2,4-dichlorobenzoic acid, the resulting acids were cyclized to chlorobenz(c)acridineswith phosphorus oxychloride, and the amine side chain introduced by heating the chloroacridines with 5-diethylamino-2-pentylamine in the presence of phenol.
1
Present address: Houdry Process Corp., Box 427, Marcus Hook, Pa. 454
455
HETEROCYCLICS FROM 4-METHOXY-1-NAPHTHYLAMINE
(S) indicates a saturated ring when the tetrahydronaphthylamine is used as the starting material. The numerals in parentheses refer to these hydrogenated compounds. It has been demonstrated that the phenory compound is an intermediate in the last step of the Atabrine synthesis (1) and in this work small amounts of the phenoxy intermediates (XII, XIV) n ere isolated n hen the reaction conditions were too mild. Benzo((h)quinoZines. A successful method of preparing benzo(h)quinolines from the naphthylamines was developed employing Mueller and Hamilton's modification (2) of the Conrad-Limpach reaction. Condensation of the amines with sodium ethyl ethoxalylacetate gave compounds which were readily cyclized by heating in mineral oil. Saponification, decarboxylation, and chlorination then yielded chlorobenzo(h)quinolines which vere treated with 3diethylaminopropylamine to obtain the desired products. S x h compounds without the 6-methoxyl group have been described in a patent (3) as possessing antinalarial activity.
COzCaHs
I
'NHZ C1-
N=C CH2 C 02 Cz Ha
XozcZHs
oi 1 250"
4- Na+ -0 =CHC02C2Hs +
I
OCHa
___3
I
ocH3 XXIII (XVII)
456
a. BRYANT BACHMAN
AND JOHN W. WETZEL
The original plitn for the preparation of the chlorobenzo(h)quinolines involved submitting the amines to a Skraup reaction, converting the benzo(h)quinolines so obtained to N-oxides, treating these with phosphorus oxychloride and separating the resulting mixture of 2- and 4-chlorobenao(h)quinolines (4). The yields from the Skraup reaction were so poor that this approach was abandoned. 4-Methoxy-l-naphthylamine(I) used in the above syntheses was prepared by coupling alpha-naphthol with benzenediazoniuni chloride; the azo dye as reduced, acetylated, methylated, and deacetylated to produce the amine hydrochloride, which gave the free base on neutralization.
ONa
4-Methoxyd ,6 ,7 ,8-tetrahydro-l-naphthylamine(V) vas prepared by a highpressure catalytic (nickel) hydrogenation of 1-acetamido-4-methoxynaphthalene (11) in dioxane solution. The product was deacetylated t o the amine hydrochloride which gave the free base on neutralization. It was originally planned to prepare the tetrahydroamine (V) by reducing l-methosy-4-nitroso-5,6,7, 8-tetrahydronaphthalene1 but the latter compound could not be obtained. During nitrosation of l-methoxy-5 ,6 ,7 ,%tetrahydronaphthalene hydrolysis of the ether linkage occurred giving 4-nitrosod ,6 , 7 ,8tetrahydro-l-naphthol. This demethylation is similar to the reaction obeerved by Meyer and co-wo-kers ( 5 ) who found that nitrous acid acts on l-naphthyl methyl ether with 10s; of the methyl group. Pharmacological testing. Tested by oral administration three times per day
HETEROCYCLICS FROM 4-MEl"OXY-1-NAPHTHYLAMINE
457
for five days on malaria-infected ducklings only compound XXVIII showed activity (Q 0.32). Acknowledgments. We wish to express our thanks to Eli Lilly and Company and the Purdue Research Foundation for the financial support of this investigstion, and to the former for pharmacological tests. EXPERIMENTAL
4-Methozy-1-naphthylamine( I ) . Alpha-naphthol was coupled with benzene diazonium chloride and the azo dye reduced to 4-hydroxy-1 -naphthylamine hydrochloride according to the method described in Organic Syntheses (6). The product melted a t 265267" (decamp.). It was converted to 4-acetarnido-l-naphthol (7) in 75% yield by using Fieecr'a general procedure (8). hlethylation with dimethyl sulfate gave 4-acetamido-1-methoxynaphthalene (9) (11) in 90% yield. This was hydrolyzed to 4-methoxy-1-naphthylamine hydrochloride (111) [m.p. 278-279' (decomp.) from ethanol] in 90% yield by refluxing for six hours with a 1 N solution of hydrochloric acid in methanol. Neutralization of a decolorized solution of the hydrochloride with sodium carbonate gave 4-methoxy-l-naphthylamine (10). 4-Acetamido-l-methoxy-6,5,7,8-telrahydronaphthalene ( I V ) . Forty grams of I1 was dissolved in 600 ml. of dioxane and 5 g. of finely ground U.O.P. nickel catalyst added. The I1 was reduced a t 130-140" and 1500-2000 pounds hydrogen pressure. After recrystallization from ethanol, the white product melted a t 188-189"; yield 70-85%. Anal. Calc'd for C ~ ~ H I J V O C,~ 71.18; : H, 7.81. Found: C, 71.10, 71.38; H, 7.f4, 7.66. 4-Methozy-5,5,7,8-tetrahydro-l-naphthylamine ( V ) . The hydrochloride of this amino was prepared from IV by refluxing an alcoholic hydrochloric acid solution for six hours; yield of crude product 95%, m.p. 250-253" (decornp.). The free base, m.p. 61', wm obtained on neutralization. It oxidixed rapidly in air and turned purple. It was analyzed a8 the stable hycirochloride. Anal. Cslc'd for C11H&O.HCl: C, 01.82; H, 7.55. Found: C, 62.15, 61.74; H, 7.67, 7.81. It v a s originally planned t o prepare the tetrahydroamine by reducing l-methoxy-4nitroso-5,6,7,8-tetrahydronsphthalene, but the latter compound could not be obtained. During nitrosation of l-methoxy-5,6,7,8-tetrahydronaphthalene, hydrolysis of the ether linkage occurred giving 4-nitroso-5,6,7,8-tetrahydro-l-naphthol (VI) in 68.5% yield; m.p. 161-163"; literature value 163' (11). 4-Amino-6,6,7,8-tetrahydro-f -naphthol (VIZ). The moist crude nitrosonaphthol (VI), 40 g., was dissolved in 450 rnl. of conc'd ammonium hydroxide and 800 ml. of water. The reddish brown solution was filtered to remove resinous material, and hydrogen sulfide gas was bubbled into the filtrate until the precipitation of the amino compound was complete. The free base was filtered, washed with cold water, dissolved in 50 ml. of conc'd hydrochloric acid and 750 ml. of water, and decolorized. Upon reprecipitation of the amine with ammonia a white product was obtained which rapidly oxidized in air; yield 67%. A sample was purified by vacuum sublimation, m.p. 144-146" (decomp.) ; literature value 146-147' (12). 4-Acetamidc-6,5,7,8-tetrahydro-l-naphthol (VZZZ). Acetylation of VI1 was accomplished by the same procedure used to prepare 11; yield 90%, m.p. 188-189". This compound was also prepared by the cat all tic hydrogenation of 4-acetamido-lnaphthol. Twenty-eight grams was dissolved in 250 ml. of dry dioxane and 5 g. of finely ground U.O.P. nickel catalyst added. The reduction was accomplished a t 1400 pounds hydrogen pressure and 130'. The dioxane solution was reduced in volume by vacuum distillation and a 75% yield of crude material isolated. The mixed melting point of samples of the compound prepared by both methods showed no depression.
458
G . BRYANT BACHMAN AND JOHN W. WETZEL
Anal. Calc'd for C1*HlaN02:C, 70.19; H, 7.37. Found: C, 70.32, 70.44; H, 7.47,7.20. This naphthol was methylated in an alkaline solution with methyl sulfate to produce IV identical with the product obtained by reduction of 11. ~-Acetamido-l-ethoxy-6,6,7,8-tetrahydrcnaphthalene ( I X ) . The ethylation of VI11 was carried out similarly to the methylation of the same compound. The temperature of the reaction mixture had to be raised t o 40" for complete reaction. A 70% yield of crude product was obtained. Three recrystallizations from ethanol and n,ater gave a white product with m.p. 195-196'. Anal. Calc'd for ClrHlrNOz: C, 72.1; H, 8.15; N, 6.09. Found: C, 71.7, 71.9; H, 8.35, 8.22; N, 6.23, 6.26. 7,IO-Dichloro-6-methoxy-1,t, 9,4-tetrahyd~obenz(c)acridine(x).Sixteen and one-haIf grams (0.093 mole) of V, 16.2 g. (0.085 mole) of 2,4-dichlorobenzoic acid (Heyden Chemical Corporation), 12 g. of anhydrous potassium carbonate, and 0.75 g. of reduced copper powder were suspended in 100 ml. of butanol. The mixture was stirred and heated to reflux. Carbon dioxide was given off very rapidly at first but at the end of three hours the rate was slow. The addition of 1 g. more of potassium carbonate and 0.3 g. of copper-bronze powder did not cause the rate of evolution to increase. At the end of seven hours heating, 25 ml. of 20% sodium hydroxide was added and the butanol removed by steam distillation. The dark purple residue could not be decolorized; and, on cooling, a tarry mass separated, leaving the water layer practically colorless. A filterable solid waB obtained by heating to redissolve the tar and then bubbling carbon dioxide into the hot solution. The dark powder had the melting range 200-225' and was practically insoluble in organic solvents. The yield of crude 4-chloro-N-(4-methoxy-5,6,7,8-tetrahydro-l-naphthyl)anthranilic acid was 40%. Twenty-two and eight-tenths grams of crude acid and 82.5 ml. of distilled phosphorus oxychloride were refluxed and stirred for four hours. At the end of this time the volume of the solution was reduced one-half by vacuum distillation. The residue was poured slowly into a beaker containing 650 g. of ice, 500 ml. of conc'd ammonium hydroxide and 500 ml. of chloroform. After hydrolysis of the excess phosphorus oxychloride was complete, the product was isolated by extraction with three 60-ml. portions of chloroform. Decolorization, drying, and evaporation of the chloroform solution gave a crude product, which, after recrystallization from benzene-heptane, was yellow and melted at 190-191'; yield 8.8 g., 39%. Anal. Calc'd for CI~H1&l~NO: C, 65.05; H, 4.55; N , 4.22. Found: C, 65.01,65.13; H,4.48,4.52; N, 4.30,4.36. 7,l0-Dichloro-6-methozybenz(c)acridine( X I ) . The preparation of 4-chloro-N-(4methoxy-1-naphthy1)anthranilicacid from I and 2,4-dichlorobenzoic acid followed the same procedure used with the hydrogenated amine. The preparation of this compound was also completed starting with I11 and using a sufficient excess of potassium carbonate to liberate the amine in situ. The dark colored crude acid melted in the range 275-280" and was obtained in yields of 3540%. A white, acidic by-product, melting range 225-242", was also obtained. This was soluble in sodium bicarbonate solution and contained chlorine but no nitrogen. It was not identified. The crude anthranilic acid was treated with phosphorus oxychloride as in the preparation of X. The yellow product was recrystallized from a benzene-heptane mixture, m.p. 199-200", yield 46%. Anal. Calc'd for CI8HI1C1,NO: C, 65.86; H, 3.36; N, 4.27; C1,21.64. Found: C, 65.84, 65.79; H, 3.41, 3.36; N , 4.28, 4.36; C1, 21.56, 21.63. 10-ChZoro-6-rnethoxy-7-phenoxy-l,2, S,4-tetrahydrobenz(c)acridine ( X I I ) . A mixture Of 3.32 g. (0.01 mole) of X and 10 g. of phenol was heated in an oil-bath a t 120-125' until solution was complete. T o this hot solution was added 1.74 g. (0,011 mole) of rectified 5-diethylamino-2-pentylamine (Winthrop Chemical Company). The mixture seemed to solid-
459
HETEROCYCLICS FROM 4-METHOXY-1-NAPHTHYUMINE
ify at first but the solid soon dissolved to form a red-orange solution. Heating waR continued for three hours, and then the hot solution was poured slowly into a cold mixture of 50 ml. of ether and 50 ml. of 10% sodium hydroxide solution. A small amount of insoluble material separated and was removed by filtration. This insoluble material melted above 335' and was assumed to be the acridone resulting from hydrolysis of X, since treatment of the material with phosphorus oxychloride reconverted it to X. The remaining reaction products were separated from the alkaline solution by repeated extractions with ether. The ether extracts were dried and the ether evaporated leaving a yellowsolid. Three recrystallizations from heptane gave a product melting a t 193-195' which was shown by analysis to be the yellow phenoxy intermediate (XII). Anal. Calc'd for C24H&1NO2: C, 73.93; H , 5.17; S,3.59. Found: C, 73.93, 74.00; H, 5.21,5.18; K,3.61, 3.52. 10 - Chloro - 7 - (5 diethylarnino - 2 - pentylamino) - 5 - methory l,2,S,4 tetrahydrobenz(c)acridine dihydrochloride (XZZZ). The heptane mother liquors from the above described reaction &-ereevaporated leaving a brilliant yellow residue, m.p. 90-93", which was the desired free base in a hydrated form. This hydrate was stable at room temperature, but lost water on standing in a desiccator over calcium chloride and changed t o a gummy mass. It was not possible to obtain a crystalline sample of the anhydrous base. The mobt satisfactory procedure found for purifying the product was to recrystallize it from ethanol and water in the completely hydrated form. This material was then dissolved in ethanol and treated with hydrogen chloride gas until the solution was acid to Congo Red. Crystallization was induced by heating the ethanol solution to boiling and adding isopropyl ether to the first faint trace of cloudiness. The hydrated hydrochloride, yield 30%, was not hygroscopic, and it lost its watcr of crystallization only after prolonged heating at 140' at 15 mm. pressure in the presence of phosphorus pentoxide. This yellow hydrate showed a transition point with dehydration a t 175-158'. The residue melted a t 247-250' with decomposition. C, 61.50; H, 7.27. Anal Calc'd for C~~Hs~ClN80.2HC1: Found: C, 61.34, 61.49; H , 7.38, 7.42. 1O-Chloro-5-methoxy-7-phenoxybenz(c)acridine(XZV). 7,10-Dichloro-5-methoxybena(c)acridine (XI) was treated with 5-diethylamino-2-pentylamine in the presence of phenol in the same manner as the tetrahydro compound (X). The yellow phenoxy intermediate was isolated from this reaction as before and recrystallized from heptane, m.p. 182-183'. Anal. Calc'd for C?dH&lN02: C, 74.68; H, 4.18; N, 3.63. Found: C, 74.82, 74.73; H, 4 55, 4 60; IC,4.00, 4.09. IO-Chloro 7 - (6-diethylamzno- 2 - pentylamino)- 5 methoxybenz(c)actidine dihydrochloride (XV) The condensation of XI with 5-diethylamino-2-pentylamine was accomplished in seven hours at 135'. The yellow hydrochloride was rccrystallized from ethanol-isopropyl ether, n1.p. 233-235" (decomp.) with a transition point a t 215-216'; yield 41%. H2O: C, 60.94; H, 6.64; C1, 20.01. Anal. Calc'd for CzrH&1Ns0.2HC1. Found: C, 60.93,60.02; H , 6.81,6.77; C1,19.97,20.01. 6-Hydroxy-7,8,910-tetrahydrobenzo(h)guinoline (XVZ). Since both 4-acetamido-lmethoxyd, 6,7 ,8-tetrahydronaphthalene (IV) and 4-acetamido-1 -etlhoxy-5,6,7,8-tetrahydronaphthalene (IX) were dealkylated by the conditions of the Skraup reaction, 4-acetainid0-5,6,7 ,8-tetrahydro-l-naphthol(VIII) was used as the starting material. Thirty-one grams (0.15 mole) of VIII, 70 ml. (0.96 mole) of glycerol and 9.15 ml. (0.09 mole) of nitrobenzene were heated while stirring until complete solution was obtained. Thirty-nine ml. (0.7 mole) of conc'd sulfuric acid was added dropwise through the reflux condenser over a period of one hour. The reflux temperature gradually dropped from 144' to ?33' during three hours. The mixture was poured over ice and diluted to 500 ml. The acid-insoluble tar was filtered off, and the filtrate was neutralized with 15% sodium hydroxide solution. A grayish white precipitate that turned dark on standing formed at the neutral point. Attempts to purify this fraction by alcohol or alkali extraction were unsuccessful. However, a white solid material was obtained when the product was
-
.
-
-
-
+
-
460
G. BRYANT BACHMAN AND JOHN W.
WETZEL
distilled a t 1 mm. pressure. After three recrystallizations from alcohol, white pistee, m.p. 257-258", were obtained in 2530% yields. This material was soluble in alkali and formed a hydrochloride, m.p. 270-272' (decomp.). Anal. Calc'd for CirHiiNO: C, 78.39;H , 6.53;N , 7.04. Found: C, 78.30,78.29;H, 6.68'6.68; N, 7.05,6.98. Diethyl I-(~-methozyd,6,7,8-tetrahydro-l -naphthylimino)succinate (XVII), The procedure of Mueller and Hamilton (2)was used to condense 4-methoxy-5,6,7,8-tetrahydro-lnaphthylamine hydrochloride and sodium ethyl ethoxalylacetate. A 93% yield of a brown solid was obtained. This was purified by recrystallization from methanol-water, m.p. E4".
Anal. Calc'd for CipHaEr'Oi: C, 65.67;H, 7.26. Found: C, 65.31,65.65;H, 7.36,7.34. R-Carbethozy-4-hydrozy-6-methoz~-7,8,9, IO-tetrahydrobenzo(h)guinoline (XVIII) . Ring closure was obtained by dropping XVII into mineral oil a t 250'. The white crystalline solid that separated on cooling was washed free of oil with petroleum ether and purified for analysis by recrystallization from benzene; m.p. 212-214"; yield 75%. Anal. Calc'd for C I ~ H I ~ N C, O ~67.74; : H, 6.36. Found: C, 68.05,67.84;H, 6.55,6.35. I-Carbozy-4-hydroxy4-methoxy-7,8,9 ,10-tetrahydrobenzo(h)quinoline (XIX), Twenty grams of XVIII was suspended in 500 g. of 10% sodium hydroxide solution and the mixture was stirred and heated on the steam-bath for two hours. Acidification with hydrochloric acid gave a 90% yield of the white acid which was not very soluble in organic solvents. A sample was recrystallized from a large volume of ethanol, m.p. 263-264" (decomp.). Anal. Calc'd for C&bNOc: C, 65.90;H, 5.53. Found: C, 65.88,65.54;H, 5.62,5.55. 4-Hydrozy-6-mcthoxy-7,8,9,lO-tetrahydrobenzo(h)quinoline (XX). Two grama of XIX was ground with 0.5 g. of copper-chromite catalyst (13). The solid was heated in an oilbath preheated to 250". Ten minutes was usually sufficient time to obtain complete decarboxylation as determined by the rate of evolution of carbon dioxide. The black residue was powdered and extracted with 10 ml. of 10% sodium hydroxide solution. After filtration and decolorization, the basic solution was saturated with carbon dioxide to precipitate XX. Reprecipitation from alkali or recrystallization from ethanol-water gave a white product, m.p. 257-258', yield 60-700/0. Anal. Calc'd for ClcHIbNO*:C, 73.32;H, 6.60. Found: C, 73.46, 73.59;H , 6.72, 6.66. ~-ChZoro-6-methozy-7,8,9,l0-tetrahydrobenzo(h)quinoline (XXZ). Two grams of crude X X was heated to reflux, 105-110°, for two hours with 20 ml. of phosphorus oxychloride. Ten milliliters of the solution was removed by vacuum distillation and the residue was poured s10wly over 50 g. of ice. After hydrolysis of the excess phosphorus oxychloride a t 0', 5 ml. of conc'd hydrochloric acid was added, the solution was filtered, decolorized, and then neutralized a t 20-30" with ammonium hydroxide. The gummy precipitate solidified on standing. It was very soluble in most organic solvents. Recrystallization from methanol-water gave a white product, m.p. 107', yield 75%. Anal. Calc'd for CIdH1,ClNO: C, 67.88;H, 5.70. Found: C, 67.93,67.98;H, 5.62,5.75. 4-(S-Diethylaminoprop ylamino)-6-mefhoxy-7,8,9, IO-tetrahydrobenzo(h)quinoline dihydroChloTidt!( X X I Z ) . A mixture of 0.25 g. of XXI and 0.31 g. (100% excess) of purified 3-diethylaminopropylamine (Sharples Chemicals Inc.) was refluxed for eight hours. The product gradually solidified during the later stages of heating. The cooled solid was washed w i t h water to remove the excess amine, dissolved in ether, and extracted with 5% sodium hydroxide solution. The ether extract was then washed with dil. hydrochloric acid and the washings treated with alkali to precipitate the free base as a brown oil. An oily hydrochloride was obtained under anhydrous conditions in a n ether solution. It reprecipitated as an oil from ethanol-isopropyl ether solution and finally crystallized on long standing in
HETEROCYCLICS FROM 4-METHOXY-1-NAPHTHYLAMINE
461
the cold. Every effort to obtain a crystalline hydrated hydrochloride failed. The yellow anhydrous hydrochloride (yield 70%) melted at 252-254' (decomp.) and was very hygroscopic. Anal. Calc'd for C Z I H U N I O - ~ H CC,~ 60.86; : H, 8.03; N, 10.14. Found: C, 60.52, 60.43;H, 7.91,7.95;N, 10.07,9.98. Diethyl R-(.4-methoxy-l -naphthylimino)succinate (XXZIZ). 4-Methoxy-1-naphthylamine hydrochloride (111) was treated with sodium ethyl ethoxalylacetate according to Mueller and Hamilton's procedure (2). The yellow Schiff base (yield 85%) was purified by recrystallization from methanol, m.p. 77". Anal'. Calc'd for CtpHilNOs: C, 66.45;H, 6.17. Found: C, 66.45,66.36;H, 6.09,6.19. ~-Carbethoxy-~-hydroxy-6-methoxybenzo(h)quinoline ( X X Z V ) . XXIII was dropped into five t i x e s its weight of preheated mineral oil in the same manner aa in the preparation of XVIII. The yellow cyclized product was recrystallized from benzene; m.p. 180-181", yield ti&%. Anal. Calc'd for C~,HI&O,: C, 68.68;H, 5.09. Found: C, C8.76, 68.83;H, 5.12, 5.23. d-Carboxy-4-hyd~oxy-6-methoxybenzo(h)quinolane ( X X V ) . XXIV was hydrolyzed to the acid by treatment with 10% sodium hydroxide as in the preparation of XIX. The acid waa not very soluble in organic solvents, but a sample of the yellow compound was recrystallized for analysis from a large volume of ethanol, m.p. 253-255" (decomp.). The yield of crude acid was 7i%. An alkali-insoluble residue (20%) was also obtained. Anal. Calc'd for CljHllNO4: C, 66.91;H, 4.12. Found: C, 66.78,67.20;H, 4.36,4.28. .$-Hydroxy-6-methoxybenzo(h)guinoline( X X V Z ) , The decarboxylation of XXV was accomplished in the same manner as in the preparation of XX. The loss of carbon dioxide was not, as rapid at 250-260' as it was with XX, and increasing the temperature to 270" gave a large amount of alkali-insoluble tar. The yield of white reprecipitated material was 46.!;%. A pure sample, m.p. 269-27G9, was obtained by recrystallization from methanol-wat er. Anal. Calc'd for ClrHllNOz: C, 74.65;H, 4.92. Found: C, 74.33, 74.47; H,5.19, 5.05. .$-Chloro-6-methoxybenzo(h)quinoline ( X X V Z Z ) , Chlorination of XXVI was accomplished by using phosphorus oxychloride as in preparation of XXI. The yield of crude product was 31.5%. An analytical sample recrystallized from methanol-water waa yellow and melted at 101-102". Anal, Calc'd for C14Hli~ClNO: C, 68.99;H, 4.14. Found: C, 68.76, 68.77; H, 4.27, 4.27. ~-(S-~iethylarninopropylam~no) -6-methozybenzo(h)quinolins dihydrochloride ( X X V I I Z ) . XXVII was heated with a n excess of purified 3-diethylaminopropylaine for eight hours. The product was worked up in a manner similar to that used for XXII. It was impossible to obtain a solid free base but the yellow anhydrous hydrochloride melted at 246-248' (decomp.), yield 70%. Anal. Calc'd for CzlHSrNsO.2HCl: C, 61.46;H, 7.10; N, 10.24. Found: C, 61.22, 61.10; H, 6.96,7.07; N, 10.09, 10.02. Efhyl 3- (C-meth~xy-6,6,7,8-te/rahyd~o-l -naphlhylamino)crotonate ( X X I X ) A solution of 3.37 g. (0.02 mole) of 4-methoxy-5,6,7,8-tetrahydro-l-naphthylamine (V) in 4.0 g. (0.03 mole) of ethyl acetoacetate waa allowed to stand sixteen hours at room temperature. The mixture fiist becaae cold but gradually warmed and finally had t o be cooled. An immiscible layer of mater separated and was removed. The product was dissolved in ether and the solution was extracted three times with 5% sodium hydroxide solution, washed with water t o remove excess base, and dried. A dark brown solid was obtained from the ether, which, after recrystallization from ethanol and water, became white and melted at 81-82', yield 70%. I
462
G. BRYANT BACHMAN AND JOHN W. WETZEL
Anal. Calc’d for ClrHzZNOa: C, 70.59; H, 7.96. Found: C, 70.54, 70.43; H, 8.04, 8.14. ~-Hydroxy-6-methoxy-~-methyl-7,8,9,lO-tstrahydrobenzo(h)quinoline(XXX). Eighteen and three-tenths grams of XXIX was added slowly with stirring to 150 g. of paraffin oil preheated to 260’. The mixture was heated for five minutes after all foaming had ceased, then cooled, and the crystalline solid filtered out and washed with petroleum ether until free of oil. A 78.5% yield of crude material which melted 5’ low, was isolated. The analytical sample recrystallized from methanol-mater was white and melted at 273’. Anal. Calc’d for CX.HI,NO~:C, 74.03; H , 7.05. Found: C, 74.04, 74.32; H, 7.19, 7.11. 4-Chloro-6-methozy-9-methyl-7’,8,9, IO-tetrahydrobenzo(h)quinoline (XXXI). A mixture of 5.53 g. (0.025 mole) of XXX and 32 ml. of phosphorus oxychloride was refluxed for four hours. The excess phosphorus oxychloride was removed under reduced pressure, and the residue was poured into a mixture of 200 g. of ice. 150 ml. of ammonium hydroxide, and 150 ml. of chloroform. The chloroform layer was separated after the phosphorus oxychloride had completely hydrolyzed. The aqueous layer was extracted with fresh chloroform, and the extracts mere combined and dried by shaking with calcium chloride. The chloroform was removed by distillation and left a dark residue (yield 51.5%). A sample purified for analysis by recrystallization from methanol was white and melted at 104-105’. Anal. Calc’d for ClsH&lNO: C, 68.81; H, 6.17. Found: C, 68.99, 69.19; H, 6.17, 6.24. SUMMARY
4-Methoxy-1-naphthylamine and 4-methoxy-5,6,7,8-tetrahydro-l-naphthylamine have been used as starting materials to prepare heterocyclic compounds of pharmaceutical interest. Benz (c)acridine benzologs of Atabrine, and 4-diethylaminopropylaminobenzo(h)quinolines have been prepared from the amines. LAFAYETTE, IND. REFERENCES MAQIDSON AND GRIQOROVSKII, Ber., 69, 396 (1936). AND HAMILTON, J . Am. Chem. Soc., 66,860 (1944); 66, 1017 (1943). MUELLER ANDERSAG AND BREITNER, U. S. Patent 2,231844 (Feb. 11, 1941). BACHMAN AND COOPER, J . Org. Chem., 9, 302 (1944). MEYERAND LENKARDT, Ann., 398, 74 (1913). MEYER,IRSCHICH, AND SCHLOSSER, Ber., 47, 1741 (1914). (6) Ory. Syntheses, Coll. Vol. 1, 49 (1941); Coll. Vol. 2, 39 (1943). (7) LIEBICH AND NEUNHOEFFER, Ber., 71, 2247 (1938). (8) FIESER,“Experiments in Organic Chemistry”, p. 165 (1941). D. C. Heath and Co., New York. AND SMITH, J . Chem. Soc., 671 (1935). (9) HODGSON (10) WROSKZOW, Chem. Zentr., 83, 11, 611 (1911). (11) ROWEAND LEVIN,J . Chem. SOC.,530 (1927). (12) SCHROETER, et al., Ann., 426, 153 (1922). (13) Org. Syntheses, 19, 31 (1933). (1) (2) (3) (4) (5)
