SOME?-SUBSTITUTED BENZOQUINOLINE DERIVATIVES
July, 1946
NEW COMPOUND 2-( 4-Diethylamino-l-methylbutylamino)-4hydroryquinazolinel 2-Chloro-4-methoxyquinazoline2(3.0 g.) and 4.8 g. of purified !oval diamine’ were heated two and a half hours a t 125-130 . The thick oil was dissolved in 40 cc. of 6 N hydrochloric acid and the solution heated six hours on the steam-bath. Then 20 cc. of concentrated hydrochloric acid was added and thesolution allowed to stand overnight. The solution was made strongly alkaline with sodium hydroxide, and was extracted with ether. Between the ether and aqueous layers there was a considerable layer of a (1) This work was done under a contract recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Rochester. (2) Lange Rmbh and Asheck THISJOURNAL, Sa, 3699 (1930). 7 IilnPs I n < l Eng ~ ’ 1 ~ 7 f t A7inl Ed 16, 431 (1944)
[CONTRIBUTION FROM THE
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thick red-brown oil. The aqueous layer was saturated with carbon dioxide gas; a gummy white solid separated. I t was picked out and dissolved in acetone, while the carbonate solution was extracted with ether. The ether and acetone solutions were combined and evaporated to dryness, and the residue sublimed in a high vacuum with the temperature of the oil-bath surrounding the sublimation apparatus a t 100-150 . The creamy-white crystalline sublimate of the quinazoline derivative melted a t 165167’; yield, 0.44 g. (9.5%). The product from another run was purified by r:peated sublimation. White crystals, m. p. 177.5-181 , were obtained. Anal. Calcd. for C I , H ~ ~ O NC, ~ : 67.51; €1, 8.67. Found: C, 67.64; H, 8.69. Samples of this compound melted as a rule at about 90°, then resolidified and melted again a t the temperatures reported above. UNIVERSITY OF ROCHESTER ROCHESTER, NEW YORK J. F. BUNNETT RECEIVED APRIL5, 1946
AVERYLABORATORY OF CHEMISTRY
OF THE UNIVERSITY OF XEBRASKA]
Some 7-Substituted Benzoquinoline Derivatives’ BY ROBERTE. FOSTER, ROBERTD. LIPSCOMB,THEOS. 3. THOMPSON? AND CLIFFS.HA MILT ON^ In a continuation of the study of derivatives of benzoquinolines which has been carried on in this L a b ~ r a t o r y ,the ~ syntheses of 4-chlorobenzo(h)I quinoline and I-chlorobenzo(f)quinoline have been carried out by the method of Price and R ~ b e r t s . ~ In addition, the former compound has been synI 11 thesized by an alternative method employing ethyl ethoxalylacetate, and derivatives of both chloro compounds have been prepared. The synthesis of 4-~hlorobenzo(h)quinolineinvolved initially the condensation of ethyl ethoxymethylenemalonate with l-naphthylamine to give ethyl 2-naphthylaminomethylenemalonate (I). 111 IV V vI Cyclization of (I) in phenyl ether a t 250’ gave actly analogous manner starting with 2-naphthyl3-carbethoxy-4-hydroxybenzo(h)quinoline (11) which yielded 3-carboxy-4-hydroxybenzo(h)quin- amine. I n the synthesis involving ethyl ethoxalylaceoline (111) upon hydrolysis in alkaline solution. When the acid (111) was heated near its melting tate, the initial condensation with l-naphthylpoint, carbon dioxide was evolved and 4-hydroxy- amine yielded ethyl 1-naphthyliminosuccinate benzo(h)quinoline (IV) was obtained. Conver- (VII). This compound was cyclized in mineral sion of this product to 4-chlorobenzo(h)quinoline oil a t 230’ to yield an isomer of 11, namely, 2(V) was readily accomplished by treatment with a carbethoxy-4-hydroxybenzo(h)quinoline (VIII). mixture of phosphorus oxychloride and phos- This ester was converted to the corresponding acid phorus pentachloride. The synthesis of 1-chloro- by alkaline hydrolysis; subsequent decarboxylabenzo(f)quinoline (VI) was carried out in an ex- tion yielded 4-hydroxybenzo(h)quinoline (11’).
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(1) A part of the work described in this manuscript was done under contract OEMsr-85, recommended by the National Defense Kesearch Committee, between the Office of Scientific Research and Uevelopment and the Board of Regents of the University of Nebraska. (2) Part of the work described io this paper was taken from a thesis submitted to the graduate faculty of the University of Nebraska hy Theos. J . Tnompson in partial fulfillment of the requirements for the degree of Master of Science. (3) Responsible: investigator. (4) For preceding commiinications see Gobeil and Hamilton, TI113 J O U R N A L , 87, 511 (1945).
( 5 ) Price and Roberts, ibid., 68, 1208 (1946).
The over-all yield of 7-chlorobenzoquinoline prepared by either method was above 35%. The method using ethyl ethoxyiiiethylenenlalonate
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R. E.FOSTER, R. D. LIPSCOMB, T.J. THOMPSON AND c. s. HAMILTON
Vol. 68
gave higher yields in the preparation of these the temperature of the solution held at 245-252" for twenty minutes. T a n crystals separated when the soluparticular compounds. tion was allowed t o cool and were collected on a filter and Condensation of V was accomplished with washed several times with petroleum ether; yield, 92 g. ammonia, morpholine, piperidine, y-N-morpho- (82%). A sample recrystallized from glacial acetic acid linopropylamine, -y-diethylaminopropylamine,6- melted at 261-265'. Anal. Calcd. for Cl~HlaO~N:C, 71.89; H , 4.90. diethylaminobutylamine, and 4-amino-1-diethylaminopentane. In addition, VI was condensed Found: C, 71.91; H, 5.15. 3-Carboxy-4-hydroxybenzo(h)quinoline (III).-The with 4-amino-1-diethylaminopentane. h)quinoline (150.7 9.) crude 3-carbethoxy-4-hydroxybenzo( The attempted condensation of V with 4-amino- from the preceding step was refluxed with 1000 ml. of 5% 1-diethylarninopentane in the presence of alco- sodium hydroxide solution for forty-five minutes. The hot holic alkali yielded only 4-ethoxybenzo(h)quino- solution was acidified with dilute hydrochloric acid, and precipitated solid was isolated on a filter, washed with line and the reaction of V with an acidified aque- the water, and dried. The yield of the Nude acid was 127.5 g. ous solution of 4-ainino-l-diethylaminopentane, (94.846). The acid could be purified b y dissolving i t in a boiling in a manner similar to that of Banks,' resulted in hydrolysis of V to 4-hydroxybenzo(h)quinoIine dilute solution of potassium bicarbonate, filtering hot, and reprecipitating with dilute hydrochloric acid; fine white, (I\'). powdery crystals were thus obtained; m.p. 291-292" (d.)
Experimental*
All melting points were corrected for exposed thermometer stem. Ethyl 1-Naphthylaminomethylenemalonate (I).-A solution of 185 8 g. ( 0 G mole) of l-naphthylamine'and 129.6 g. (0 G mole) of ethyl ethoxymethylenemalonate wa6 placed in vacuo and dry air bubbled through the reaction mixture overnight. The solidified material was melted and again placed in Z'(ICUOt o remove more completely the ethanol genarated. The dark gray solid could be utilized in the next step of the synthesis without purification. Crystallized twice from ethanol, the ani1 appeared as white tetragonal platelets; m. p. 87.5-88.0'. A w l . Calcd. for ClsH190rN: C, 68.99; H , 6.11. FOUiId: C, 68.93; H, 6.351 Ethyl 2-Naphthylaminomethylenemalonate.-This compottiid was prepared in an exactly analogous tnanner. The yield of colorless product which was crystallized from niethanol was WYi.; in. p. 76-78.5'. A n a l . Calcd. for ClsH1504~: C, 68.99; H , 6.11. Found: C, 68.88; H, 6.11. 3-Carbethoxy-4-hydroxybenzo(h)quinoline (II).-The cycl-z:itioii 1 \ 3 5 carrictl out in a flask fitted with a steamjriclxtctl coiidcii\c.r which allowed the ethanol generatcd diiriiig thc reaction to escape. T.ie crude ethyl 1-naphthylaminomethyleneinalonate \vas melted and added to 350 ml. of boiling phenyl ether. The solutioi! was refluxed for fifty minutes, during which tiine the teiiiperature of the refluxing vapors rose from 200 t o 237". l h c solution was then allowed t o cool. The crutle protluct was separated from the phenyl ether by filtratioii, triturated three times with low-boiling petroleum cther to remove thc phenyl ether, and dried. The yield o f ihe liro\\w, crutle ?-carbethoxy-4-hydroxybenzo(h)qniiioliiie. 111. p. 2,77-259 , was 150.7 g. or 94yo based on 1naphthylaniinc and ethyl ethoxymethylenenialonate. Tiis ester was soluble in dilute hydrochloric acid, and illsoluble i n dilute alkali; the niaterial was very slightly solulile i i i alcohol, acetone, and toluene. Fine, fluffy, crea.ii-colorcd iieedles were obtained by crystallization froni acetic acid; in.p. 261-262'. A j i o I . Calctl. for Cd11303K: C, 71.89; €1, 4.00. FOUI C ] : C, i2.15; I i , 5.11. 2-Carbethoxy-l-hydroxybenzo(f)quinoline.---To 220 m l . o f I~uiliiigpheiiyl ctliet- i n a round-bottomed flask fitted with ail air-coolvtl cuiideiiicr was added 131 g. (0.42 mole) of inelted ethyl 2-naphthylaniinoniethylenrmalonate and ( t i ) T h e prepar!itioii < > f 1 c l i l i , r c , b e n z o ~ f ) q u i n ~ , l i n by e t h e ethyl cthi,..:ilylacet;ite inethnil a n d the preparation
